Cambios en el manejo del CM precoz Perspectivas de futuro ......Perspectivas de futuro para esta...

#SEOM20

Cambios en el manejo del CM precoz Perspectivas de futuro para esta nueva época

Sara López-Tarruella

Employment: Hospital General Universitario Gregorio Marañón & Universidad Complutense de Madrid

Consultant or Advisory Role: Celgene, Novartis, Pierre Fabre, Pfizer, Roche, Astra-Zeneca, Eisai and Lilly

Stock Ownership: NA

Research Funding (clinical trial participation as PI): Novartis, Genentech, SeaGen and Daiichi-Sankyo

Speaking: Novartis, Roche, Lilly

Grant support: NA

Other: NA

Disclosure Information

#SEOM20

The changing role of Neo_Adjuvant treatment in eBC

Colomer et al Oncologist 2019; Cain et al Clin Oncol 2017; Bardia et al CCR focus 2013

• NA treatment has become a preferred option for eBC treatment based on proven efficacy vs adjuvant, research value and cost perspective

• Multidisciplinary Tumor Boards are crucial to ID candidates – Pathological evaluation standardization is needed

• ADVANTAGES of NA treatment: 1. Reduces tumor size which facilitates surgical

resectability higer BCS rates & it can eliminate axillary node mets that may be detected in SLNB after NA (surgery de-escalation)

2. Enables objective evaluation of treatment efficacy, allowing an in vivo test of cancer cells’ sensitivity to treatment (RD-guided treatment after NA)

3. Allows the design of CTs that offer advantages compared with the adjuvant setting (lower sample size, early results, biomarkers, new CT designs) (new drug development strattegies)

#SEOM20

Neo_Adjuvant treatment in eBC: response & prognosis

Cortazar et al Lancet 2014; Spring et al CCR 2020

• Cortazar et al pooled analysis (12 CTs; 11955 pts) pCR (ypT0 /is ypN0) after NACT associated with improved EFS and OS (individual level) but no established trial level correlation pCR and long-term outcomes

• Strongest association pCR and long-term outcome in aggressive tumor types: TNBC (EFS: HR 0.24) and HER2+HR- Tz treated (EFS: HR 0.15)

• Relationship 𝛥pCR and corresponding 𝛥EFS has not been well established at trial level

CTNeoBC analysis (2014) Comprehensive Meta-analysis (2020)

• 52 studies (27895 pts): 51.1% CTs, 42.8% retrospective studies; 6.1% single arm trials. Median FU for recurrence: 48 mo. Median FU for survival: 49.9 mo

• Pts who had pCR vs those with residual disease had significantly better EFS (HR 0.31), for TNBC (HR 0.18) and HER2+ (HR 0.32)

• Pts who had pCR vs those with residual disease had significantly better OS (HR 0.22)

• 5-year EFS in patients with pCR followed by adjuvant CT 86% vs pCR without additional adjuvant CT 88% pCR after NACT likely reflects tumor biology and suggests adjuvant CT could potentially be omitted in certain circumstances

Overall TNBC

HER2+

#SEOM20 Balko et al Nature Med 2012 and Cancer Discov 2014; Caparica et al Ther Adv Med Oncol 2019

The management of Residual Disease after NA treatment

• Comprehensive molecular analyses on the residual disease after NACT (combined NGS and digital RNA expression) identified diverse molecular lesions and pathway activation in the drug-resistant component of the tumor, which may mirror micro-metastases destined to recur

• Profiling of residual BC after NACT identifies i.e. DUSP4 deficiency (MAPK phosphatase) as a mechanism of drug resistance

• Data can guide biomarker-driven adjuvant studies targeting these micrometastases to improve the outcome of patients with TNBC who do not respond completely to NACT

Targetable alterations and pathways in TNBCs after NACT

Potential strategies to manage RD post_NA

#SEOM20

Adjuvant Post-NA treatment in TNBC

Masuda et al NEJM 2017

Pts 20-74 yrs of age with stage I-IIIB HER2-BC and residual disease (non-pCR, N+) after

NACT* and surgery; ECOG PS 0 or 1; no

previous oral fluoropyrimidines (N = 910)

Capecitabine 2500 mg/m²/day PO Days 1-14

Q3W for 8 cycles‡

Hormonal therapy if ER/PgR+

(n = 455)

HT if ER/PgR+No further therapy if ER/PgR-

(n = 455)

St rat if ied by ER stat us, age, NACT, use of 5-FU,

inst it ut ion, node st at us

§ Primary endpoint: DFS

§ Secondary endpoints: OS, time from first day of preoperative CT to recurrence or death, safety, cost-effectiveness

NACT Surgery• Pathology

Non-pCR or

• Node +

Adjuvant CT

CREATE-X trial

The Adjuvant post-NA treatment: a second “chance”?

Masuda et al NEJM 2017; Von Minckwitz et al NEJM 2018

CREATE-X KATHERINE

69.8% vs 56.1% 78.8% vs 70.3%

#SEOM20

What about NA treatment in HR+ HER2- BC? NET

Guerrero et la Cancer Discov; Cardoso et la Ann Oncol 2019; Thorton et al Ann Surg Oncol 2019

• NET emerges as an attractive option to optimize surgical outcomes: option for CT unfit/ineligible for surgery elderly pts (alternative options) biology driven designs to develop new targeted strategies in luminal BC

• Facts and open-questions: Patient selection: biology guided, post- vs premenopausal? Optimal NET regimen: IA > TAM and posible new combinations with targeted therapies (CDK4/6inh or PI3K /Akt/mTOR inh)? Treatment duration: pCR rates increase with treatment duration (4-8mo)? Evaluation of response: pCR limited value in ER+ disease, Ki 67 suppression/PEPI score?

#SEOM20 Careful look to the biology behind to optimize the algorithm for eBC… Harbeck et al Nature Reviews Disease Primers 2019; Burstein et al Ann Onccol 2019

Late Recurrrences (luminal): Extended adjuvant ET

Early Recurrrences (luminal): ET+CDK4/6 inh

Non-pCR (TNBC/HER2): Adjuvant post-NA strategies (T-DM1/Capecitabine…)

TILs (TNBC): no CT

Multiparameter classif. (HER2+): CT de-escalation

Low/Intermediate risk GEP (luminal): no CT

Tailoring eBC treatment: from the ”add-on” to “de-escalation” strategies

#SEOM20

Let’s take a careful look to the biology behind

Metzger-Filho et al JCO 2013; Cheng et al Cancer Epidemiol Biomarkers Prev 2012; Foulket et al NEJM 2010; Harbeck et al Nature Rev Disease Primers 2019; Rueda et al Nature 2019

Late relapsing ER positive subtypes

Subtype-specific risks of relapse at the time of diagnosis

#SEOM20


Early Recurrrences (luminal): ET+CDK4/6 inh

Trial ID Design Population 1

Endpoint Start-LPFV

PENELOPE_B GBG78/BIG 1-13/NSABP-B-54-I NCT01864746

PALBO125 mg x13 +ET vs Placebo x13 +ET

N=1250 HR+/HER2- No PCR after NACT CPS-EG>3 or 2 and ypN+

iDFS 2014-2017

PALLAS AFT-05/ABCSG 42/BIG 14-03 NCT02513394

PALBO125 mg x24mo +ET vs SOC (ET at least 5yr)

N=5796 HR+/HER2- stage II (IIA limited to 1000 pts)-III

iDFS

2015-2018

monarchE I3Y-MC-JPCF/ NSABP B-58 NCT03155997

ABEMA150mg BIDx24mo+ET vs SOC (ET)

N=4580 HR+/HER2-: N>4+ OR N 1-3+ and T>5cm; G3; Ki67 central>20%)

iDFS

2017-2019

NATALEE CLEE011O12301C NCT03701334

RIBO400mg x36mo +ET* vs ET* *ET=NSAI +goserelin in PreM

N=5000 (4000) HR+/HER2-stage IIB-III or IIA N1 or N0 G3/G2/ki>20%/Oncotype>26/Mammaprint/Prosigna/Endopredict High risk

iDFS

2018-

CDK4/6 inhibitors in the adjuvant setting for HR+HER2- eBC

#SEOM20

CDK4/6 inhibitors in the adjuvant setting for HR+HER2- eBC: Palbociclib

Mayer et al ESMO 2020

PALLAS Eligibility

• Stage II or III invasive breast cancer

• Estrogen receptor (ER) and/or progesterone receptor (PR) positive, HER2 negative (HER2-), by

local laboratory assessment

• Completed definitive breast surgery, neo/adjuvant chemotherapy and/or radiotherapy, if indicated

• Standard adjuvant ET (tamoxifen, AI, +/- concurrent LHRH agonist) had to be initiated within 12

months of diagnosis; enrollment was within 6 months of initiating adjuvant ET

• Receipt of an FFPE tumor tissue block at a central biorepository required prior to randomization.

PALLAS: Patient Characteristics

• Between 9/2015 and 11/2018, 5,760 patients were

randomized and included in the ITT set.

• The majority had higher stage disease and had

received prior chemotherapy.

• 58·7% had high clinical risk disease, described as:

– >4 nodes involved (>N2), or

– 1-3 nodes with either T3/T4 and/or grade 3

disease.

VariablePalbociclib

+ ET (N=2,883)ET (N=2,877)

Age (y) – median (range) 52 (25 – 90) 52 (22 – 85)

Stage

IIA 504 (17·5%) 509 (17·7%)

IIB 968 (33·6%) 951 (33·1%)

III 1402 (48·6%) 1408 (48·9%)

T-Stage

T0/T1/Tis/TX 557 (19·3%) 500 (17·4%)

T2 1603 (55·6%) 1636 (56·9%)

T3/T4 722 (25·0%) 741 (25·8%)

N-Stage

N0 367 (12·7%) 383 (13·3%)

N1 1427 (49·5%) 1415 (49·2%)

N2 703 (24·4%) 709 (24·6%)

N3 385 (13·4%) 370 (12·9%)

Histologic Grade

G1 300 (10·4%) 313 (10·9%)

G2 1622 (56·3%) 1658 (57·6%)

G3 836 (29·0%) 767 (26·7%)

Prior Chemotherapy 2384 (82·7%) 2370 (82·4%)

Initial Adjuvant Endocrine Therapy

Aromatase inhibitor 1954 (67·8%) 1918 (66·7%)

Tamoxifen 923 (32·0%) 949 (33·0%)

Concurrent Adjuvant LHRH Agonist 532 (18·5%) 604 (21.1%)

PALLAS: Patient Characteristics

• Between 9/2015 and 11/2018, 5,760 patients were

randomized and included in the ITT set.

• The majority had higher stage disease and had

received prior chemotherapy.

• 58·7% had high clinical risk disease, described as:

– >4 nodes involved (>N2), or

– 1-3 nodes with either T3/T4 and/or grade 3

disease.

VariablePalbociclib

+ ET (N=2,883)ET (N=2,877)

Age (y) – median (range) 52 (25 – 90) 52 (22 – 85)

Stage

IIA 504 (17·5%) 509 (17·7%)

IIB 968 (33·6%) 951 (33·1%)

III 1402 (48·6%) 1408 (48·9%)

T-Stage

T0/T1/Tis/TX 557 (19·3%) 500 (17·4%)

T2 1603 (55·6%) 1636 (56·9%)

T3/T4 722 (25·0%) 741 (25·8%)

N-Stage

N0 367 (12·7%) 383 (13·3%)

N1 1427 (49·5%) 1415 (49·2%)

N2 703 (24·4%) 709 (24·6%)

N3 385 (13·4%) 370 (12·9%)

Histologic Grade

G1 300 (10·4%) 313 (10·9%)

G2 1622 (56·3%) 1658 (57·6%)

G3 836 (29·0%) 767 (26·7%)

Prior Chemotherapy 2384 (82·7%) 2370 (82·4%)

Initial Adjuvant Endocrine Therapy

Aromatase inhibitor 1954 (67·8%) 1918 (66·7%)

Tamoxifen 923 (32·0%) 949 (33·0%)

Concurrent Adjuvant LHRH Agonist 532 (18·5%) 604 (21.1%)

#SEOM20



#SEOM20


PALLAS: Dose Reductions

Time to first palbociclib dose reduction

Cumulative proportion of patients requiring at least one palbociclib dose reduction

Dose Level 6 mo 12 mo 18 mo 24 mo

100 mg 42.2% 48.9% 53.5% 55.4%

75 mg 17.3% 25.9% 30.5% 34.3%

PALLAS: Tolerability

• Treatment-emergent adverse events

occurred in 99·4% on palbociclib + ET vs

88·6% on ET alone

• Grade 3/4 neutropenia was common with

palbociclib + ET vs ET alone (61.3% vs

0.4%); febrile neutropenia was

uncommon (1.0%)

• Other all-grade toxicities more common

with palbociclib + ET included

hematologic, fatigue, upper respiratory

tract infection, nausea/diarrhea, alopecia.

Adverse Events, incidence >15% Adverse Event Palbociclib + ET (N=2,840) ET (N=2,903)

All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4Any adverse event 2822 (99·4%) 1897 (66·8%) 159 (5·6%) 2571 (88·6%) 400 (13·8%) 24 (0·8%)

Neutropenia 2354 (82·9%) 1620 (57·0%) 122 (4·3%) 139 (4·8%) 11 (0·4%) 0

Leukopenia 1550 (54·6%) 843 (29·7%) 14 (0·5%) 213 (7·3%) 3 (0·1%) 0

Fatigue 1150 (40·5%) 60 (2·1%) 0 546 (18·8%) 10 (0·3%) 0

Arthralgia 992 (34·9%) 30 (1·1%) 0 1207 (41·6%) 31 (1·1%) 0

Upper respiratory tract infection

805 (28·3%) 32 (1·1%) 0 453 (15·6%) 3 (0·1%) 0

Hot flush 693 (24·4%) 7 (0·2%) 0 838 (28·9%) 7 (0·2%) 0

Anaemia 664 (23·4%) 13 (0·5%) 0 157 (5·4%) 4 (0·1%) 0

Thrombocytopenia 609 (21·4%) 25 (0·9%) 1 (0·0%) 49 (1·7%) 1 (0·0%) 0

Nausea 543 (19·1%) 8 (0·3%) 0 240 (8·3%) 4 (0·1%) 0

Alopecia 496 (17·5%) 0 0 144 (5·0%) 0 0

Diarrhoea 468 (16·5%) 21 (0·7%) 0 145 (5·0%) 5 (0·2%) 0

Headache 435 (15·3%) 7 (0·2%) 0 322 (11·1%) 7 (0·2%) 0

Safety population: Patients who initiated palbociclib vs. patients who initiated ET only

PALLAS: Tolerability

• No new safety signals were identified with palbociclib + ET.

• No treatment-related deaths were observed.

• SAEs occurred in 351 (12·4%) on palbociclib + ET versus 220 (7·6%) on ET alone.

• The most common SAEs on palbociclib + ET were tissue infection, upper respiratory tract

infection, and pneumonia.

PALLAS: Exposure and Discontinuation

• Rates of palbociclib discontinuation were

closely monitored; active efforts including

outreach and education were ongoing

throughout the trial to reduce non-protocol

related discontinuation.

• At time of data cut-off:

– 725 (25·5%) were still receiving palbociclib

– 916 (32·3%) had completed planned protocol therapy

– 1199 (42·2%) had discontinued prematurely

PALLAS: Reasons for Discontinuation

• The majority of palbociclib early

discontinuation was related to

adverse events, for example,

persistent grade 3/4 neutropenia

despite dose reduction.

• The rate of early discontinuation of

adjuvant ET at 24 months was 6·9%,

with no significant difference between

arms.

Patient Status Palbociclib + ET ET

Initiated Palbociclib 2840

Ongoing Palbociclib at data cutoff 725 (25·5%)

Completed Palbociclib per protocol 916 (32·3%)

Early discontinuation of Palbociclib 1199 (42·2%)

Adverse event (including unacceptable toxicity) 770 (64·2%)

Patient non-compliance/non-adherence 128 (10·7%)

Development of recurrent disease/secondary

malignancy

104 (8·7%)

Informed consent withdrawal 100 (8·3%)

Other reasons 97 (8·1%)

Initiated ET 2840 2903

Ongoing ET at data cutoff 2462 (86·7%) 2500 (86·1%)

Ongoing ET at end of study participation 182 (6·4%) 219 (7·5%)

Early discontinuation of ET 196 (6·9%) 184 (6·3%)

Development of recurrent disease/secondary

malignancy

86 (43·9%) 84 (45·7%)

Informed consent withdrawal 49 (25·0%) 39 (21·2%)

Adverse event (including unacceptable toxicity) 28 (14·3%) 23 (12·5%)

Patient non-compliance/non-adherence 12 (6·1%) 10 (5·4%)

Other reasons 21 (10·7%) 28 (15·2%)

Tolerability Discontinuation (and reasons)

Dose Reductions


#SEOM20

CDK4/6 inhibitors in the adjuvant setting for HR+HER2- eBC: Abemaciclib

Analysis populations and disposition

Median follow up at the interim analysis: ~15.5 months in each arm

o 12.5% of patients had completed the 2-year treatment period

o Over 70% of patients were still in 2-year treatment period

N = 2808 N = 2829ITT population

n = 2791 n = 2800Received study treatment

(Safety population)

Abemaciclib + ET ET Alone

monarchE study design

Primary Objective: Invasive disease-free survival (STEEP criteria)

Key Secondary Objectives: Distant relapse-free survival, Overall

survival, Safety, Patient reported outcomes, and Pharmacokinetics

HR+, HER2-, high risk early

breast cancer

High risk defined as:

• ≥4 positive axillary lymph nodes (ALN)

OR

• 1-3 ALN and at least 1 of the below:o Tumor size ≥5 cm

o Histologic grade 3o Centrally tested Ki67 ≥20%

Other criteria:

• Women or men • Pre-/ postmenopausal

• With or without prior

adjuvant/neoadjuvant chemotherapy

• No distant metastases

Abemaciclib (150mg twice daily for up to 2 yearsb)

+ Standard of Care Endocrine Therapy(5 to 10 years as clinically indicated)

Standard of Care Endocrine Therapyb

(5 to 10 years as clinically indicated)Stratified for:

• Prior chemotherapy• Menopausal status

• Region

N = 5637a

R 1:1

Endocrine therapy of physician’s choice

aRecruitment from July 2017 to August 2019; bTreatment period = first 2 years on study treatment after randomization

Statistical considerations

Control arm 5-year IDFS rate for this high risk population was estimated at 82.5% 3,7,8

Study was powered at ~85%, assuming a hazard ratio (HR) of 0.73 for IDFS, at a cumulative 2-sided alpha level of 0.05

o This requires approximately 390 IDFS events at the time of primary analysis

Pre-planned efficacy interim analysis

o Target was approximately 75% of total required IDFS events

o 323 IDFS events were observed in the ITT population a

o A positive study required 2-sided p-value < 0.0264 b based on the actual observed number of IDFS events

3 Mamounas EP et al. Breast Cancer Res Treat 2018;168:69-77; 7 Gluz O et al. J Clin Oncol 2016; 34:2341-9; 8 Marme F et al. Eur J Cancer 2016; 53:65-74

aData cutoff March 16, 2020; bCalculated using Lan-Demets method with O’Brien−Fleming type stopping boundary

Johnston et al ESMO 2020

monarchE study design

Primary Objective: Invasive disease-free survival (STEEP criteria)

Key Secondary Objectives: Distant relapse-free survival, Overall

survival, Safety, Patient reported outcomes, and Pharmacokinetics

HR+, HER2-, high risk early

breast cancer

High risk defined as:

• ≥4 positive axillary lymph nodes (ALN)

OR

• 1-3 ALN and at least 1 of the below:o Tumor size ≥5 cm

o Histologic grade 3o Centrally tested Ki67 ≥20%

Other criteria:

• Women or men • Pre-/ postmenopausal

• With or without prior

adjuvant/neoadjuvant chemotherapy

• No distant metastases

Abemaciclib (150mg twice daily for up to 2 yearsb)

+ Standard of Care Endocrine Therapy(5 to 10 years as clinically indicated)

Standard of Care Endocrine Therapyb

(5 to 10 years as clinically indicated)Stratified for:

• Prior chemotherapy• Menopausal status

• Region

N = 5637a

R 1:1

Endocrine therapy of physician’s choice

aRecruitment from July 2017 to August 2019; bTreatment period = first 2 years on study treatment after randomization

#SEOM20



Patient demographics

Age Median (range) 51 (23-89) 51 (22-86)

Age categories<65 years 2371 (84.4) 2416 (85.4)

≥65 years 437 (15.6) 413 (14.6)

GenderFemale 2787 (99.3) 2814 (99.5)

Male 21 (0.7) 15 (0.5)

Region a

North America/Europe 1470 (52.4) 1479 (52.3)

Asia 574 (20.4) 582 (20.6)

Other 764 (27.2) 768 (27.1)

Menopausal status aPremenopausal 1221 (43.5) 1232 (43.5)

Postmenopausal 1587 (56.5) 1597 (56.5)

Prior treatment a

Neoadjuvant chemotherapy 1039 (37.0) 1048 (37.0)

Adjuvant chemotherapy 1642 (58.5) 1647 (58.2)

No chemotherapy 127 (4.5) 134 (4.7)

Baseline ECOG PS0 2405 (85.7) 2369 (83.8)

1 401 (14.3) 455 (16.1)

Note: where values do not add up to 100%, remaining data are missing, unavailable or could not be assessed; a per Interactive Web Response System (IWRS)

Abemaciclib + ET

N = 2808, n (%)

ET Alone

N = 2829, n (%)

High risk disease characteristics

Note: where values do not add up to 100%, remaining data are missing, unavailable or could not be assessed

Number of positive

lymph nodes

0 7 (0.2) 7 (0.2)

1-3 1119 (39.9) 1143 (40.4)

≥4 or more 1680 (59.8) 1679 (59.3)

Histological grade

Grade 1 209 (7.4) 215 (7.6)

Grade 2 1373 (48.9) 1395 (49.3)

Grade 3 1090 (38.8) 1066 (37.7)

Primary tumor size

by pathology

following definitive

surgery

<2 cm 780 (27.8) 765 (27.0)

2-5 cm 1369 (48.8) 1419 (50.2)

≥5 cm 610 (21.7) 612 (21.6)

Central Ki-67

<20% 953 (33.9) 973 (34.4)

≥20% 1262 (44.9) 1233 (43.6)

Unavailable 593 (21.1) 623 (22.0)

Progesterone

receptor status

Positive 2421 (86.2) 2453 (86.7)

Negative 298 (10.6) 294 (10.4)

Additional high risk

eligibility criteria for patients with 1-3 nodes

Tumor size ≥5 cm (pathology) a 249 (8.9) 236 (8.3)

Tumor size ≥5 cm (imaging) a, b 152 (5.4) 158 (5.6)

Histologic grade 3 a 629 (22.4) 618 (21.8)

Central Ki-67 ≥20% only c 216 (7.7) 237 (8.4)

Abemaciclib + ET

N=2808, n (%)

ET Alone

N=2829, n (%)

Abemaciclib + ET

N=2808, n (%)

ET Alone

N=2829, n (%)

aPatients could be counted in more than one of the sub-categories

under 1-3 positive lymph nodes; b Patients who received

neoadjuvant chemotherapy may have been eligible based on

imaging tumor size prior to receiving systemic therapy; c Patients not double counted; patients did not have tumor size ≥5 cm (either

by pathology or imaging) or histologic grade 3



Number of positive

lymph nodes

0 7 (0.2) 7 (0.2)

1-3 1119 (39.9) 1143 (40.4)

≥4 or more 1680 (59.8) 1679 (59.3)

Histological grade

Grade 1 209 (7.4) 215 (7.6)

Grade 2 1373 (48.9) 1395 (49.3)

Grade 3 1090 (38.8) 1066 (37.7)

Primary tumor size

by pathology


surgery

<2 cm 780 (27.8) 765 (27.0)

2-5 cm 1369 (48.8) 1419 (50.2)

≥5 cm 610 (21.7) 612 (21.6)

Central Ki-67

<20% 953 (33.9) 973 (34.4)

≥20% 1262 (44.9) 1233 (43.6)

Unavailable 593 (21.1) 623 (22.0)

Progesterone

receptor status

Positive 2421 (86.2) 2453 (86.7)

Negative 298 (10.6) 294 (10.4)






Central Ki-67 ≥20% only c 216 (7.7) 237 (8.4)

Abemaciclib + ET

N=2808, n (%)

ET Alone

N=2829, n (%)

Abemaciclib + ET

N=2808, n (%)

ET Alone

N=2829, n (%)

aPatients could be counted in more than one of the sub-categories under 1-3 positive lymph nodes; b Patients who received

neoadjuvant chemotherapy may have been eligible based on

imaging tumor size prior to receiving systemic therapy; c Patients not double counted; patients did not have tumor size ≥5 cm (either

by pathology or imaging) or histologic grade 3First on-study endocrine therapy

Tamoxifen

Plus ovarian suppression (any time)

857 (30.7)

192 (6.9)

898 (32.1)

232 (8.3)

Toremifene 6 (0.2) 11 (0.4)

Aromatase Inhibitors


1928 (69.1)

410 (14.7)

1891 (67.5)

386 (13.8)

Letrozole 1092 (39.1) 1046 (37.4)

Anastrozole 611 (21.9) 617 (22.0)

Exemestane 225 (8.1) 228 (8.1)

Abemaciclib + ET

N = 2808, n (%)

ET Alone

N = 2829, n (%)

First on-study endocrine therapy

Tamoxifen


857 (30.7)

192 (6.9)

898 (32.1)

232 (8.3)

Toremifene 6 (0.2) 11 (0.4)

Aromatase Inhibitors


1928 (69.1)

410 (14.7)

1891 (67.5)

386 (13.8)

Letrozole 1092 (39.1) 1046 (37.4)

Anastrozole 611 (21.9) 617 (22.0)

Exemestane 225 (8.1) 228 (8.1)

Abemaciclib + ET

N = 2808, n (%)

ET Alone

N = 2829, n (%)



Number of positive

lymph nodes

0 7 (0.2) 7 (0.2)

1-3 1119 (39.9) 1143 (40.4)

≥4 or more 1680 (59.8) 1679 (59.3)

Histological grade

Grade 1 209 (7.4) 215 (7.6)

Grade 2 1373 (48.9) 1395 (49.3)

Grade 3 1090 (38.8) 1066 (37.7)

Primary tumor size

by pathology


surgery

<2 cm 780 (27.8) 765 (27.0)

2-5 cm 1369 (48.8) 1419 (50.2)

≥5 cm 610 (21.7) 612 (21.6)

Central Ki-67

<20% 953 (33.9) 973 (34.4)

≥20% 1262 (44.9) 1233 (43.6)

Unavailable 593 (21.1) 623 (22.0)

Progesterone

receptor status

Positive 2421 (86.2) 2453 (86.7)

Negative 298 (10.6) 294 (10.4)






Central Ki-67 ≥20% only c 216 (7.7) 237 (8.4)

Abemaciclib + ET

N=2808, n (%)

ET Alone

N=2829, n (%)

Abemaciclib + ET

N=2808, n (%)

ET Alone

N=2829, n (%)

aPatients could be counted in more than one of the sub-categories under 1-3 positive lymph nodes; b Patients who received

neoadjuvant chemotherapy may have been eligible based on imaging tumor size prior to receiving systemic therapy; c Patients not double counted; patients did not have tumor size ≥5 cm (either

by pathology or imaging) or histologic grade 3

#SEOM20



Invasive disease-free survival

Two-year IDFS rates were 92.2% (abemaciclib + ET arm) and 88.7% (ET arm) – 3.5% absolute difference

Number of IDFS events


136 187

p = 0.0096 (2-sided)

HR (95% CI): 0.747 (0.598, 0.932)

Relative risk of invasive disease

reduced by 25.3%

IDFS in prespecified subgroupsIDFS in prespecified subgroups

#SEOM20

Distant recurrence locations

Locations of distant recurrence (any time) 92 142

Bone 32 81

Liver 29 42

Lung 21 21

Brain 13 16

Lymph node 7 13

Pleura 6 7

Central nervous system 4 2

Soft tissue 1 1

Skin 1 0

Peritoneum 0 1

Other b 11 7

Abemaciclib + ET

N = 2808 a

ET Alone

N = 2829 a

a Some patients were counted more than once in subcategories if they had recurrence at different locations (for example, if a patient had liver and bone metastases identified at the same time); b Includes ovarian (2), suprarenal, left scapula, abdomen, submandibular lesion, spleen, epidural, left adnexal mass, neck, fallopian tubes, adrenal (2), pericardial effusion, left orbit, spine, colon, gallbladder



Distant relapse-free survival

Two-year DRFS rates were 93.6% (abemaciclib + ET arm) and 90.3% (ET arm) – 3.3% absolute difference.

DRFS benefit consistent across all prespecified subgroups.

Number of IDFS events


106 152

p = 0.0085 (2-sided)

HR (95% CI): 0.717 (0.559, 0.920)

Relative risk of distant

recurrence reduced by 28.3%

#SEOM20



Other events of interest, any grade

VTE 63 (2.3%) 14 (0.5%)

PE 25 (0.9%) 3 (0.1%)

ILD 75 (2.7%) 33 (1.2%)

Febrile neutropenia 7 (0.3%) 1 (<0.1%)

Treatment emergent adverse events

Abbreviations: VTE = venous thromboembolic event; PE = pulmonary embolism; ILD = Interstitial lung disease

Abemaciclib + ETN = 2791,

n (%)

ET AloneN = 2800,

n (%)

Diarrhea over time

CTCAE gradingG1: <4 stools over baseline/day

G2: 4-6 stools over baseline/dayG3: >6 stools over baseline/day

Median Durations

Onset = 8 days

Grade 2 = 6 days

Grade 3 = 5 days

Diarrhea frequency and severity decreases significantly over time and very few patients discontinued due to diarrhea (4.8%)

Treatment exposure

Safety Population Abemaciclib ET ET

Number of patients who

received drug, n (%)2788 (99.9) 2791 (100.0) 2800 (100.0)

Duration on therapy,

median months14.0 14.9 15.2

Median duration on abemaciclib will continue to increase.

Study is ongoing and follow-up data will be presented subsequently.

• 463 (16.6%) patients discontinued abemaciclib due to AEs (306 remained on ET when abemaciclib was

discontinued) • In the control arm, 21 patients (0.8%) discontinued ET due to AEs

Abemaciclib + ET

N = 2791, n (%)

ET Alone

N = 2800, n (%)

Treatment exposure

Safety Population Abemaciclib ET ET

Number of patients who

received drug, n (%)2788 (99.9) 2791 (100.0) 2800 (100.0)

Duration on therapy,

median months14.0 14.9 15.2

Median duration on abemaciclib will continue to increase.

Study is ongoing and follow-up data will be presented subsequently.

• 463 (16.6%) patients discontinued abemaciclib due to AEs (306 remained on ET when abemaciclib was

discontinued) • In the control arm, 21 patients (0.8%) discontinued ET due to AEs

Abemaciclib + ET

N = 2791, n (%)

ET Alone

N = 2800, n (%)

Other events of interest, any grade

VTE 63 (2.3%) 14 (0.5%)

PE 25 (0.9%) 3 (0.1%)

ILD 75 (2.7%) 33 (1.2%)

Febrile neutropenia 7 (0.3%) 1 (<0.1%)

Treatment emergent adverse events

Abbreviations: VTE = venous thromboembolic event; PE = pulmonary embolism; ILD = Interstitial lung disease

Abemaciclib + ETN = 2791,

n (%)

ET AloneN = 2800,

n (%)

Diarrhea over time

CTCAE gradingG1: <4 stools over baseline/day

G2: 4-6 stools over baseline/dayG3: >6 stools over baseline/day

Median Durations

Onset = 8 days

Grade 2 = 6 days

Grade 3 = 5 days

Diarrhea frequency and severity decreases significantly over time and very few patients discontinued due to diarrhea (4.8%)

#SEOM20

Late Recurrrences (luminal): Extended adjuvant ET


Richman et al NRCO 2019; Rowling et al JNCI Cancer Spectrum 2019

Conclusions

Published online 18 December 2018

CTS5 result

Lowclinical risk

Lowgenomic risk

StopendocrinetherapyPatient unlikely

to benefit and potential toxicity issues

Considerextendedendocrinetherapy

Recommendextendedendocrinetherapy

Intermediategenomic risk

Highgenomic risk

Intermediateclinical risk

Highclinical risk

Borderline

Borderline

Completed5 yearsendocrinetherapy

Calculate CTS5

No genomic test required (patient unlikely to benefit from extended endocrine therapy)

Stop endocrine therapy

Recommend extended endocrine therapy

Genomic test result

Offer genomic test for late recurrence (e.g. PAM50, BCI or EPClin) Risk of late

recurrence might be great enough to justify extended endocrine therapy

Risk of late recurrence high enough to warrant extended endocrine therapy

No genomic test required; extended endocrine therapy should be offered

Fig. 4 | Decision-making aid for clinical and genomic testing. The clinical treatment score at 5 years (CTS5) should be

calculated for all women upon completion of 5 years of adjuvant endocrine therapy. For the majority of women with a low

clinical risk score, endocrine therapy can be discontinued because extended therapy is very unlikely to benefit them. For

the majority of women with a high risk of recurrence, extended endocrine therapy up to 10 years is recommended if the

toxicity profile is not unfavourable. In both situations, genomic testing is unlikely to add further prognostic information

and is not recommended. Women with an intermediate clinical risk and those at borderline low–intermediate or high–

intermediate clinical risk should receive a genomic test to enable integrated clinical–genomic stratification of their risk

of late recurrence. Following genomic testing, the following scenarios are possible: discontinuation of endocrine therapy

for patients with a low risk of recurrence or recommendation of extended endocrine therapy for up to 10 years in

patients with a high risk. Women who remain at an intermediate level of risk should discuss toxicities and personal

preferences with their clinician. Of note, the role of genomic testing as a predictor of benefit from extended endocrine

therapy remains to be established in prospective studies. BCI, Breast Cancer Index.

NATURE REVIEWS | CLINICAL ONCOLOGY

REVIEWS

VOLUME 16 | MAY 2019 | 309

#SEOM20


Prat et al Lancet Oncol 2020 & SABCS 2019

GEP selection (luminal): ET+ Targeted Therapy (CDK 4/6 inh) NA treatment

CORALLEEN

“Molecular downstaging” concept

1 endpoint: proportion of pts with low-ROR disease after NA treatment by PAM50

#SEOM20


TILs as a biomarker (TNBC): no CT

Could sTILs ID a favorable subgroup of early-stage TNBC with excellent prognosis, for whom adjuvant CT might not be necessary so could be de-escalated? (N=476 pts/4 institutions)

• Pts with sTILs ≥ 30% (29% pts) showed favorable outcomes irrespective of nodal status, suggesting a significant role of immune engagement for better survival

• sTILs ≥ 30% in p Stage I TNBC identified an excellent prognostic subgroup (5Y OSR: 98%), in whom absolute survival benefits of adjuvant CT could be minimal, with regards to associated risks and comorbidities

• Routine evaluation of sTILs should be considered for adequate prognostication and tailoring of adjuvant CT certainly in selective very low-stage early TNBC

• Pts <40 years, diagnosed with TanyN0M0 BC (1989-2000) selected from Netherlands Cancer Registry and no CT (N=481) PARADIGM study group

• Subsequent investigations to de-escalate systemic therapy in a subgroup of young TNBC patients may be warranted.

Park et al Ann Oncol 2019 and De Jong et al ESMO 2020

#SEOM20


Veeraraghavan et al ASCO 2020 and Puzstai L ASCO 2020

Multiparameter classif. (HER2+): CT de-escalation

• New molecular classifiers can ID pts who will benefit from HER2 targeted therapy alone and discriminate “degrees” of HER2 positivity (pCR prediction comparable to CT+dual antiHER2 in unselected pts) vs not prospective validation needed

#SEOM20

Tailoring eBC treatment: is there any chance to detect MRD?

Garcia Murillas et al JAMA Oncol 2019 & Sci Translational Med 2015; Ponde et al Nat Rev Clin Oncol 2019

• Personalized ctDNA assay based on digital PCR to track muts over time in pts with eBC could define the genetic events of MRD, and MRD sequencing predicted the genetic events of the subsequent metastatic relapse more accurately than sequencing of the primary BC

• Prospective validation (N=101 and 35.5 mo median FU) of molecular relapse detection Detection of ctDNA during FU associated with relapse (HR 25.2) Detection of ctDNA at diagnosis associated with RFS (HR 5.8) ctDNA detection had median lead time of 10.7 mo vs clinical relapse

(brain only mets less detected by ctDNA)

#SEOM20

CONCLUSIONES Cambios en el manejo del CM precoz: perspectivas de futuro para esta

nueva época

⦿ El uso de tratamiento sistémico adyuvante ha impactado significativamente en la supervivencia de las pacientes con CM precoz en los últimos 40 años (estrategia aditiva), pero la escalada en los regímenes de tratamiento ha aumentado las toxicidades y el costo, el objetivo hoy se centra en optimizar el balance riesgo/beneficio para cada paciente (estrategia individualizada)

⦿ El conocimiento de la biología del CM aplicado a la enfermedad precoz esta ayudando a individualizar el tratamiento del CM pe. plataformas genómicas para definir la estrategia de terapia sistémica adyuvante en pacientes con CM RH+ HER2- ha permitido el “de-escalado” de QT en pacientes con CM de bajo riesgo (TailorX, MINDACT, PlanB)

⦿ Recientemente la inclusión de fármacos innovadores como la inmunoterapia en CMTN (NA) o inh CDK4/6 en CM luminal (adyuvancia) demuestra aportar beneficio en el contexto de estrategias de “escalado” terapéutico en enfermedad precoz para pacientes con CM de alto riesgo (IMpassion031, KN522, MonarchE)

⦿ El enfoque neoadyuvante se convierte en la estrategia preferida para subtipos con CMTN y HER2+ ofreciendo información pronóstica que puede ayudar a ajustar el tratamiento adyuvante posterior en función de la respuesta (CREATE-X, KATHERINE), permitiendo abordajes loco-regionales más conservadores, constituyendo una valiosa plataforma para el desarrollo de nuevas terapias

⦿ El análisis de biomarcadores en tejido/biopsia líquida (CTCs, ctDNA) aporta resultados esperanzadores en los distintos subtipos de CM como herramienta para la individualización del tratamiento (neo)adyuvante. Su validación implica adaptar el diseño de los ensayos clínicos (i.e.BRE18-334 PERSEVERE) y un importante esfuerzo de colaboración internacional para abordar poblaciones de pacientes cada vez más circunscritas

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