current standards and practice changing studies in early ...€¦ · ihc translation of molecular...

Current standards and practice changing studies in Early Breast Cancer in 2018

F. Cardoso, MDDirector, Breast Unit, Champalimaud Clinical Center, Lisbon, Portugal

ESMO Board of Directors & Membership DirectorABC Global Alliance Chair

DISCLOSURES

Financial disclosures: Personal financial interest in form of consultancy role for: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, prIME Oncology, Roche, Sanofi, Seattle Genetics, Teva.

Institutional financial support for clinical trials from: Amgen, Astra-Zeneca, Boehringer-Ingelheim, Bristol-Myers-Squibb, Daiichi, Eisai, Fresenius GmbH, Genentech, GlaxoSmithKline, Ipsen, Incyte, Nektar Therapeutics, Nerviano, Novartis, Macrogenics, Medigene, MedImmune, Merck, Millenium, Pfizer, Pierre-Fabre, Roche, Sanofi-Aventis, Sonus, Tigris, Wilex, Wyeth.

Non-Financial disclosures: Chair ABC Global Alliance and ABC Consensus Conference and Guidelines. Member/Committee Member of ESMO, ESO, EORTC-BCG, IBCSG, SOLTI, ASCO, AACR, EACR, SIS, ASPIC

Bray et al, CA Cancer J Clin 2018;0:9–31; Globocan 2018

CANCER AS CAUSE OF DEATH

Bray et al, CA Cancer J Clin 2018;0:9–31Globcan 2018

CANCER IN WOMEN – Incidence and Mortality

GLOBOCAN 2018*

Incidence

Mortality

5-year Prevalence

BREAST CANCER WORLDWIDE

* Bray F et al. Global cancer statistics 2018: GLOBOCAN

estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018.

GLOBOCAN 2018*

5-year Prevalence

BREAST CANCER IN AFRICA

* Bray F et al. Global cancer statistics 2018: GLOBOCAN

estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018.

Incidence

Mortality

EBC OUTCOME EVOLUTION

Breast Cancer

Despite ↑ incidence - ↓ mortality

* Screening & early diagnosis

* Education & advocacy

but also

* Better treatment options

* Better treatment strategies

St. Gallen 2017Escalating and de-escalating treatment in Early Breast Cancer across subtypes

and treatment modalities

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (“Oxford Overview”)

ESMO Early Breast Cancer Guidelines 2015

Is the difference between the curves clinically significant?

89.8%

89.4%

DFS Absolute difference 0.4%

96.1%

95.7%

Invasive DFS Absolute difference 2.3%

CLINICOPATHOLOGICAL PROGNOSTIC FACTORS IN EBC

• Tumor size

• Lymph node status

• Grade

• ER, PR and HER-2 receptor expression

• Presence of lymphovascular invasion

PROGNOSTIC VALUE OF BC MOLECULAR SUBTYPES

IHC TRANSLATION OF MOLECULAR CLASSIFICATION

ER/PR HER2 PCAD CK5 EGFR CK14

LUMINAL A

LUMINAL B

HER 2 OE

BASAL

Courtesy of MJ Brito

PROGNOSTIC VALUE OF SUBTYPES IHC SURROGATES

Dent et al, Clin Cancer Res, 2007

CRUCIAL ROLE OF HIGH QUALITY PATHOLOGY(and also cost-effective!)

8th Edition AJCC: ANATOMIC and PROGNOSTIC STAGGING

7th

Edition Stage

Tumor Size

Nodal Involvement

Metastasis

13

8th Edition Prognostic

Stage Group

Tumor Size

Nodal Involvement

Metastasis

ER/PR/HER2

Tumor Grade

Low risk GES

2010-2017 2018 and beyond

WHO NEEDS TREATMENT? WHICH TREATMENT IS BEST?

TREATMENT CHOICES

AVOID UNDER AND OVER TREATMENT INDIVIDUALIZE TREATMENT

2 MAIN QUESTIONS NEEDED TO BE ANSWERED

New/better PROGNOSTIC FACTORS New/better PREDICTIVE FACTORS

HER2

Negative predictive value

(<5% chance to respond to anti-estrogens or trastuzumab)

HIGH 95%

Positive predictive value

30-50%

Breast Cancer

ER/PGR

VALIDATED PREDICTIVE MARKERS

Cut off 1%

Courtesy F. Penault-Llorca

IHC Algorithm

When to question a Pathology report… according to Frédérique Penault-Llorca

• PgR+, ER-

• Lobular, tubular carcinoma HER2+

• Grade 1, ER+++, PgR+++, HER2+

• Grade 3, ER-, ki67 <5%

• Grade 3 ER+++, PgR+++

• Medullary carcinoma is extremely rare and has been removed from WHO classification

May redo HER2 (and ER) on surgical specimen if grade 3, ER- or ER+

If ER and/or PgR is negative on a biopsy redo on surgical specimen

MULTIDISCIPLINARY CARE IS CRUCIAL!

EARLY BREAST CANCER: WHO NEEDS ADJUVANT CT?

Bedard & Cardoso, Nat. Rev. Clin. Oncol. 8, 272–279 (2011)

• CLINICAL/PATHOLOGICAL/GENOMIC FACTORS ARE BEST USED IN COMBINATION.

• Responsiveness is a continuum.• PATIENT PREFERENCE!

TAILORx Methods: Treatment Assignment & RandomizationAccrued between April 2006 – October 2010

Preregister – Oncotype DX RS (N=11,232)

Register (N=10,273)

ARM A: Low RS 0-10

(N=1629 evaluable)

ASSIGN

Endocrine Therapy (ET)

Mid-Range RS 11-25

(N=6711 evaluable)

RANDOMIZEStratification Factors: Menopausal

Status, Planned Chemotherapy, Planned Radiation, and RS 11-15, 16-20, 21-25

ARM B: Experimental Arm

(N=3399)

ET Alone

ARM C: Standard Arm

(N=3312)

Chemo and ET

ARM D: High RS 26-100

(N=1389 evaluable)

ASSIGN

Chemo and ET

Joseph A. Sparano, MD

2

0

TAILORx Results - ITT Population: All Arms (A,B,C & D)

IDFS

P<0.001

Joseph A. Sparano, MD

RS 0-10: Assigned to ET Alone

RS 11-25: Randomized to ET Alone

RS 11-25: Randomized to CHEMO + ET

RS 25-100: Assigned to CHEMO + ET

9-Year Event Rates

• RS 0-10 (Arm A)

• 3% distant recurrence with ET

alone

• RS 11-25 (Arms B & C)

• 5% distant recurrence rate overall

• < 1% difference for all endpoints

• IDFS (83.3 vs. 84.3%)

• DRFI (94.5 vs. 95.0%)

• RFI (92.2 vs. 92.9%)

• OS (93.9 vs. 93.8%)

• RS 26-100 (Arm D)

• 13% distant recurrence despite

chemo + ET

GENOMIC TESTS IN ALL OR ONLY SELECTED BREAST CANCER CASES?

TRIPLE NEGATIVE(ER-, PR-, HER-2 neg)

CT indispensible

HER-2 POSITIVE

CT + anti-HERindispensible

LUMINALER+ HER-2 neg

“Clear” indication from classical factors

All LOW risk: high levels ER, PR, grade 1, node

negative, low proliferation

HT alone

All HIGH risk: low levels ER, PR, grade 3, node

positive, high proliferation

CT HT

“No Clear” indication from classical factors; some high

& some low risk

GENOMIC TEST

CRUCIAL IMPORTANCE OF HIGH QUALITY PATHOLOGY

Practical use of Mammaprint® in the clinic based on evidence from the MINDACT trial

HR+ tumor:Define clinical risk

Clinical “low” risk* Clinical “high” risk

Treatment according to guidelines

Discuss with patient if she would value a 1.5% gain in DMFS with adjuvant chemotherapy

No

Order Mammaprint

Yes

Proceed with chemotherapy

Courtesy M. Piccart

PREOPERATIVE CHEMOTHERAPY IN BCHISTORICAL PERSPECTIVE

1970 1980 1990 2000

Locally advanced

Early Early Early

GOAL

DISEASE

Local control Rate of breastconservation

Survival Treatment tailoring

ACHIEVED NO DIFFERENCEACHIEVED ONGOING

Adapted from M. Piccart

EBCTCG Neoadjuvant vs Adjuvant CT. Lancet Oncology 2017

Substantially higher frequency of BCS with

neoadjuvant

Association between pCR and EFS by BC subtype

Cortazar P et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBCpooled analysis. Lancet. 2014

The magnitude of improvement in pCR ratedid not predict EFS and OS effect

Cortazar P et al. Pathological complete response and long-term clinical

benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014

Efficacy of adjuvant CT compared with no CT

Risk of recurrence Breast cancer mortality Overall mortality

Anthracycline based regimen vs no CT

RR:0.73, 95%CI

Absolute gain: 8%

RR:0.79, 95%CI

Absolute gain: 6.5%

RR:0.84, 95%CI

Absolute gain: 5%

CMF regimen vs no CT

RR:0.70, 95%CI

Absolute gain: 10.2%

RR:0.76, 95%CI

Absolute gain: 6.2%

RR:0.84, 95%CI

Absolute gain: 4.7%

Messages from the EBCTCG overview & individual trials

Ribeiro, Sousa and Cardoso, ECCO-ESMO 2013 Educational Book

EBCTCG 2005-06 Overview Peto SABCS 2007

10

0 5 10 0 5 10 0 5 10

50

0

40

30

20

Anthra

31.0%

Taxane

25.9%

%

+ SE

15.3

12.8

YearsYearsYears

CMF

31.3%

Anthra

27.0%

Control

36.4%

CMF

32.2%

20.5

17.8

19.9

16.5

Taxanes > Anthra > CMF > No Chemo

4.2%

4.3% 5.1%

WHICH TYPE OF CHEMOTHERAPY?

TAKE-HOME MESSAGES REGARDING (NEO)ADJUVANT CT

• For TNBC and HER-2+ Anthracyclines and Taxanes, in a sequentialregimen, are the standard.

• For Luminal A with high burden of disease justifying CT, probably it does not matter which regimen is chosen

• For Luminal B, depends on burden of disease: high burden: Anthracyclines and Taxanes: Low burden: probably ok to omit A

• Important to consider:• Long term toxicity of only 3 to 4 cycles of A is lower than the

“old” 6 cycles of FEC/FAC• No need to use 5-FU (LoE 1A)

Efficacy of 5 years Tam

WHICH TYPE OF ENDOCRINE THERAPY?



Study Treatment arms/ Population (n)

MedianFU

Recurrence Mortality

Tamoxifen 5 yearsOverview 2011[76]

TAM 5 y vs no TAM10 645 ER+

15 y RR 0.53 [SE 0.03] years 0–4

RR 0.68 [SE 0·06] years 5–9

2p<0·00001RR 0.97 [SE 0.10] years

10–14

RR 0.71 [SE 0.05] years 0–4,

RR 0.66 [SE 0.05] years 5–9

RR 0.68 [SE 0.08] years 10–14

p<0·0001

CARRY-OVER EFFECT

9% ABSOLUTE BENEFIT

MCBS: A

AI vs. TAM

Switch AI after TAMvs. TAM

Adjuvant Aromatase Inhibitors: A meta-analysis

Dowsett M et al., J Clin Oncol 2010

Recurrences Breast cancer deaths

EBCTCG, Lancet. 2005

Years

85.2

73.7

0

20

40

60

80

100

0 5 10 15

Tamoxifen

Control

15% 17%

0

20

40

60

80

100

0 5 10 15

87.8

Years

Tamoxifen

Control

9% 18%

91.4

% o

f p

ati

en

ts

% o

f p

ati

en

ts

54.9

68.2 73.0

64.0

More than Half of all Breast Cancer Recurrences

and Deaths Occur Post- 5y Tamoxifen

N Engl J Med 2017;377:1836-46

Courtesy M. Gnant, SABCS 2016

Annual Risk of Recurrence by ER Status

Saphner T et al., J Clin Oncol 1996

Hormone receptor positivity is a strong predictor for late recurrence !

• Over half of breast cancer recurrences occur >5 years post-surgery!

• The annual risk of late recurrence is particularly high in ER+ tumors (5.2%

between years 5 and 8, 4.6% between years 8 and 12).

Years

0

0.1

0.2

0.3

0 1 2 3 4 5 6 7 8 9 10 11 12

Recu

rren

ce

hazard

rate

ER– (n = 1305)

ER+ (n = 2257)

ROLE OF OFS & AI IN PREMENOPAUSAL WOMENTEXT & SOFT Trials

Francis et al, N Engl J Med, 2015

TEXT and SOFT Trials: Comparison of Tamoxifen or Exemestane With OFS

Tamoxifen 20 mg/day+ OFS* (n = 1328)

PremenopausalPatients with HR+ BC≤ 12 wks after surgery

(N = 2672)

Stratified by trial, use of chemotherapy, nodal status

*OFS TEXT: triptorelin 3.75 mg IM every

28 days for 6 mos, then optional bilateral oophorectomy or irradiation

SOFT: choice of method

TEXT

Exemestane 25 mg/day+ OFS* (n = 1014)

Tamoxifen 20 mg/day

Premenopausalpatients with HR+ BC≤ 12 wks after surgery

(if no chemo) or≤ 8 mos after chemo

(N = 3066)

SOFT

Tamoxifen + OFS*(n = 2344)

Tamoxifen 20 mg/day+ OFS* (n = 1016)

Exemestane + OFS*(n = 2346)

Exemestane 25 mg/day+ OFS* (n = 1332)

Joint Analysis

5 yrs

Pagani O, et al. ASCO 2014. Abstract LBA1.

Pagani et al, N Engl J Med, 2014

This presentation is the intellectual property of the presenter. Contact [email protected] for permission to reprint and/or distribute.

San Antonio Breast Cancer Symposium, December 9-13, 2014

Hazard Ratio of Relapse

0.5 1 1.5 2

ER+, 35+

ER-, 35+

ER+, <35

ER-, <35


0.5 1 1.5 2

ER+, 35+

ER-, 35+

ER+, <35

ER-, <35

Outcomes from Premenopausal Adjuvant Chemotherapy Trials with no Hormonal Rx

Goldhirsch A et al. JNCI Monogr 2001;30:44-51


0.5 1 1.5 2

ER+, 35+

ER-, 35+

ER+, <35

ER-, <35


0.5 1 1.5 2

ER+, 35+

ER-, 35+

ER+, <35

ER-, <35

SOFT Trial: CONCLUSIONSSTRENGTHS:

1) LARGE, PROSPECTIVE, RANDOMIZED TRIAL

2) PRAGMATIC APPROACH TO USE OF CT

3) PROVIDES EVIDENCE THAT IN SOME PATIENTS WITH BETTER PROGNOSIS TAMOXIFEN ALONE IS A VERY GOOD TREATMENT

4) GIVES SUPPORT TO USE OF OFS IF NO AMENORRHEA IS OBTAINED WITH CT

5) HELPS DEFINING THE ROLE OF AIs IN PREMENOPAUSAL PATIENS, TOGETHER WITH THE TEXT TRIAL

OPEN QUESTIONS:

1) PATIENTS RECEIVING CT (higher risk) WITH AMENORRHEA

2) PATIENTS RECOVERING MENSES AFTER 8 MONTHS

3) <35 years AND no need for CT

4) OPTIMAL DURATION OF OFS: are 5 years really necessary ?

5) WILL RESULTS CHANGE WITH LONGER FU (ER+ disease); NEED FOR OS RESULTS

TAKE HOME MESSAGES and OPEN QUESTIONS regarding ADJUVANT ET

• Ovarian suppression/ablation is indicated in pts with high risk of recurrence needing CT and recovering menses after CT. Reserve AI+OFS to very high risk only

(toxicity!)

• Decision for the individual patient still difficult; optimal duration unknown

• 5 years is the minimal duration for all patients. In pts with “sufficiently high risk” consider extended adjuvant

• Optimal duration for the individual patient is unknown; Best strategy for extended adjuvant (10 y Tam; 10 y AI, sequence, “sandwich”, …) is unknown

• TAMOXIFEN is essential. AIs provide a small additional benefit and different toxicity profile

•No predictive markers to discriminate between Tam & AI

HR

210

0.63

0.66

0.59

0.66

0.41

1.27

3.2%

2.7%*

6%

5%

6.6%*

Difference at

4y/3ya

–1.5%

3

Median

FU yrs

3

3

2

3

p

0.004

0.017

0.0115

0.07

n.s.

* Benefit at

3 y

4

Favours trastuzumab Favours chemotherapy only

Combined US (n=3969)b

HERA (n=3401)

BCIRG AC-DT (n=1074)

BCIRG DCarboT (n=1075)

FinHER (n=232)

PACS-04 (n=528)

Reference

Smith 2007

Slamon 2006

Joensuu 2006

Spielmann 2007

0.0004

aAbsolute difference in percentage of patients with OS at 4 or 3 yearsbCombined US: Joint analysis of NSABP B-31 and NCCTG N9831

Perez 2007

*Benefit at 3y

Adjuvant chemotherapy ± trastuzumab

trials: overall survival

Slamon 2006

REDUCTION IN MORTALITY RISK: 34%-59% IN EBC

COST TRASTUZUMAB: 2.300 €/cycle (s.c T)

MCBS: A

TRIALS EVALUATING ADJUVANT TRASTUZUMAB DURATION

1 vs. 2 years: HERA

9 weeks: FinHER (Finland)

1 year vs. 3 ms: E 2198 (US)

1 year vs. 9 weeks: ShortHER

1 year vs. 9 weeks: SOLD

1 year vs. 6 ms: PHARE (France)

1 year vs. 6 ms: HeCOG (Greece)

1 year vs. 6 ms: Persephone (UK)

Prof Helena Earl MD PhD

https://warwick.ac.uk/fac/med/research/ctu/trials/cancer/per

sephone

Persephone Study Design

4

4

1O : DFS [Diagnosis to 1st relapse (local or distant) or death]

2O :OS ; Cost effectiveness ; Cardiac function

4000 patients

https://warwick.ac.uk/fac/med/research/ctu/trials/cancer/persephone

DFS

Treatment delay due to cardiotoxicity: 6% (12m) vs 4% (6m), p=0.01 Treatment stopped due to cardiotoxicity: 8% (12m) vs 4% (6m), p<0.0001) Cardiac function recovers pós trastuzumab; 6m patients had a faster recovery

(p=0.02)

Persephone study

OS

TAKE HOME MESSAGES

Duration of adjuvant trastuzumab: 1 YEAR IS STILL THE STANDARD

In total about 15.000 pts enrolled to answer duration question!Really needed? Can we be smarter in trial design?

If we had done 1 trial but sufficiently powered?

BUT: PHERSEPHONE results demand discussion of shorter duration in “low risk” patients

Open questions: De-escalate anti-HER2 therapy or CT or both?How to define “low risk HER2+ BC”?Can we find a biomarker to help with the decision?

TRIALS EVALUATING DUAL HER2 BLOCKADE

Advanced DiseaseEGF104900

Cleopatra PERUSE

PHEREXA

NeoSPHERE TRYPHAENAWSG-ADAPT

KRISTINE

NeoALTTOCherlob

LPT 109096 NSABP B-41

CALGB 40601

Neoadjuvant setting

ALTTO APHINITY Adjuvant setting

STRATEGY A STRATEGY B

Alvaro Moreno-Aspitia et al, ASCO 2017

Presented by:

DISEASE-FREE SURVIVAL (DFS) ANALYSIS

*Bracketed data in all KM curves represent results of the Primary Analysis – ASCO 2014

*


Absolute difference: 2 to 3%

Presented by:

OVERALL SURVIVAL (OS) ANALYSIS


DUAL BLOCKADE COST: 5.800 €/cycle

MCBS: No Evaluable Benefit

COST LAPATINIB: 3.500 €/cycle

ALTTO trial

49The slides are the property of BIG. Permission required for reuse


APHINITY: Trial Design

Chemotherapy* + trastuzumab+ placebo

Chemotherapy* + trastuzumab+ pertuzumab

Randomisation and treatmentwithin 8 weeks of surgery

Anti-HER2 therapy for a total of 1 year (52 weeks)(concurrent with start of taxane)

Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy

Central confirmation

of HER2 status(N = 4805)

FOLLOW-UP

10

YEARS

R

S

U

R

G

E

R

Y

*A number of standard anthracycline-taxane-sequences or a non-anthracycline (TCH) regimen were allowed

G. von Minckwitz et al, ASCO 2017, NEJM 2017


A HINIT Intent to Treat rimary Endpoint Analysis Invasive isease free urvival

Number needed to treat: 112

expected: 89.2%


Absolute difference: 2 %

APHINITY trial

DUAL BLOCKADE COST: 6.400 €/cycle

MCBS: Afor Node+ or ER neg

COST PERTUZUMAB: 4.100 €/cycle


APHINITY: Node-positive Subgroup


G. von Minckwitz et al, ASCO 2017




APHINITY: Hormone Receptor-negative Subgroup


G. von Minckwitz et al, ASCO 2017


De-Escalation

Tolaney S, NEJM 2015

Timing of Distant Recurrences in relation to Adjuvant Trastuzumab

Romond EH, N Engl J Med 2005; 353:1673-1684. NSABP B-31 and NCCTG N9831

< 2% of patients relapse on adjuvant trastuzumab

and < 5% in the year following

Courtesy G. Curigliano

HR (95% CI) = 0.73 (0.57–0.92)Two-sided P = 0.008

Intention-to-treat population. Cut-off date: March 1, 2017

NeratinibPlacebo

50

60

70

80

90

0 6 12 18 24 30 36 42 48 54 60

No. at risk Neratinib Placebo

1420 1420

1316 1354

1272 1298

1225 1248

1106 1142

978 1029

965 1011

949 991

938 978

920 958

885 927

Months after randomization

Inva

sive

dis

ease

-fre

e s

urv

ival

(%

)100

95.5%∆ 2.4%

97.9%

91.7%∆ 2.6%

94.3%

90.2%∆ 2.0%

92.2%

89.1%

∆ 2.1%

91.2%

87.7%∆ 2.5%

90.2%

0

Treatment

ExteNET: 5-year analysis: iDFS

M. Martin et al, ESMO 2017

Absolute difference: 3.5 %

ExteNET: Side Effects

Chan i wsp. Abst.508

N % Neratinib (n=14080) Placebo (n=1408)

All grades G3-4 All grades G3-4

Diarrhea 1343 (95.4) 562 (39,9) 499 (35,4) 23 (1,6)

Dose reduction: 26%

Tx termination: 17%

What does G 3 diarrhea mean ?- > 7 stools daily- incontinence;

-hospitalization indicated- limiting self care ADL

Courtesy of Dr Aleksandra Łacko

NEWER NEOADJUVANT TRIALS IN HER-2+ EBC

Trying to differentiate HER2+/ER+ from HER2+/ER neg

The biological complexity of HER2+ breast cancer

mRNA microRNA Protein

DNA Copy Number DNA Methylation DNA Mutations

HER2+ tumor cells features

TCGA Nature 2012

HER2+ disease today

HER2 +3 HER2 ISH+

ER-positive ER-negative

Courtesy of Dr. Pedro Fernández

HER2+ tumor microenviroment

Tumor Infiltrating

Lymphocytes(TILs)

Courtesy Aleix Prat, EBCC 11

pCR by Central ER/PR Receptor Status

Presented by:

pC

R(%

)a

ER and PR negative ER and/or PR positive

60/82 45/83 56/128 46/131

TCH+P T-DM1+P TCH+P T-DM1+P

aypT0/is, ypN0; patients with missing or unevaluable pCR status were considered nonresponders. Twenty patients had “unknown” ER/PR status by

central analysis.

Difference (95% CI):

−19.0 (−33.3, −4.6)

Difference (95% CI):

−8.6 (−20.5, 3.2)

73%

54%

44%35%

KRISTINE

ADAPT HER2+/HR+ Trial

ar eck et al. A C 2015. A stract 5 0 .

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

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 ≥ 0%in -wk biopsy.

THE ROLE OF T-DM1 IN EBC(neoadjuvant)

• Similar pCR rates with T-DM1 alone or with T-DM1 + Pertuzumab

• In line with Marianne in ABC HER2+• Why dual blockade with T-DM1 + P

does not seem to work??!

• Good pCR in Triple + EBC

San Antonio Breast Cancer Symposium December 4–8, 2018

KATHERINE Study Design

This presentation is the intellectual property of Charles E. Geyer Jr. Contact him at [email protected] for permission to reprint and/or distribute.

cT1-4/N0-3/M0 at presentation (cT1a-b/N0 excluded)

Centrally confirmed HER2-positive breast cancer

Neoadjuvant therapy must have consisted of

– Minimum of 6 cycles of chemotherapy

• Minimum of 9 weeks of taxane

• Anthracyclines and alkylating agents allowed

• All chemotherapy prior to surgery

– Minimum of 9 weeks of trastuzumab

• Second HER2-targeted agent allowed

Residual invasive tumor in breast or axillary nodes

Randomization within 12 weeks of surgery

Stratification factors:

Clinical presentation: Inoperable (stage cT4 or cN2–3) vs operable (stages cT1-3N0-1)

Hormone receptor: ER or PR positive vs ER negative and PR negative/unknown

Preoperative therapy: Trastuzumab vs trastuzumab plus other HER2-targeted therapy

Pathological nodal status after neoadjuvant therapy: Positive vs negative/not done

T-DM1

3.6 mg/kg IV Q3W

14 cycles

Trastuzumab

6 mg/kg IV Q3W

14 cycles

Radiation and endocrine therapy per protocol and local guidelines

R

1:1

N=1486

THE ROLE OF T-DM1 IN EBC(post-neoadjuvant)


Invasive Disease-Free Survival


100

80

60

40

20

0

743

743

No. at Risk

Trastuzumab

T-DM1676

707

635

681

594

658

555

633

501

561

342

409

220

255

119

142

38

44

4

4

0 6 12 18 24 30

Time (months)

Invasiv

e D

isease

-Fre

e S

urv

ival R

ate

(%

)

36 42 48 54 60

Trastuzumab

T-DM1

3-year IDFS 77.0% 88.3%

Trastuzumab T-DM1

(n=743) (n=743)

IDFS Events, no. (%) 165 (22.2) 91 (12.2)

P<0.0001

Unstratified HR=0.50 (95% CI, 0.39–0.64)


Distant Recurrence


743

743

No. at Risk

Trastuzumab

T-DM1679

707

643

682

609

661

577

636

520

564

359

412

233

254

126

143

41

45

4

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Dis

tant

Re

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ence-F

ree R

ate

(%

)

Trastuzumab

T-DM1

Trastuzumab T-DM1

(n=743) (n=743)

Events, no. (%) 121 (16.3) 78 (10.5)

Unstratified HR=0.60 (95% CI, 0.45–0.79)

3-year event-free rate 83.0% 89.7%

100

80

60

40

20

0

0 6 12 18 24 30

Time (months)

36 42 48 54 60

THE ROLE OF T-DM1 IN EBC(post-neoadjuvant)

MAIN PROBLEM:COST!!

Absolute difference: 11% in iDFS

Biosimilar trastuzumab in Phase 3 clinical trials: setting and primary endpoint

*Non-inferiority margin. NA, not available

1. Amgen press release. June 2016. Available at: http://www.amgen.com/media/news-releases; 2. NCT01901146. Available at:

https://clinicaltrials.gov/ct2/show/NCT01901146; 3. Shustova M, et al. Ann Oncol 2016;27(Suppl 6):vi68–vi99; 4. Im Y-H, et al. ASCO 2013; Abstract and poster

presentation 629; 5. NCT02162667. Available at: https://clinicaltrials.gov/ct2/show/NCT02162667; 6. Rugo HS, et al. JAMA 2017;317:37–47;

7. NCT02149524. Available at: https://clinicaltrials.gov/ct2/show/NCT02149524; 8. NCT01989676. Available at: https://clinicaltrials.gov/ct2/show/NCT01989676;

9. NCT02187744. Available at: https://clinicaltrials.gov/ct2/show/NCT02187744. All websites accessed March 2017.

Trastuzumab

biosimilarPatients Setting Primary endpoint Equivalence margins

ABP 9801,2 827Neoadjuvant + adjuvant in

EBC (includes switch)pCR (breast + lymph)

EMA: -13%, 13% with 90% CI for pCR

difference

FDA: 0.758 to 1.318 with a 90% CI for pCR

ratio

BCD-0223 126 MBC ORR -20%* with 95% CI for ORR difference

CT-P64 475 MBC ORR-15%, +15% with 95% CI for

ORR difference

CT-P65 562Neoadjuvant + adjuvant in

EBCpCR (breast + lymph) NA

MYL-1401O6 500 MBC ORR at Week 24

EMA: -15%, 15% with 95% CI for

ORR difference

FDA: 0.81 to 1.24 with a 90% CI for ORR ratio

SB37 806 Neoadjuvant in EBC pCR (breast only) NA

PF-052800148 690 MBC ORR NA

PF-052800149 226 Neoadjuvant in EBC Powered for PK endpoints NA

Courtesy M. Thill

TAKE HOME MESSAGES regarding HER2+ EBC

• Trastuzumab is life-saving and has changed the natural history of HER2+ EBC! (should be the focus of lobbying/pressure for access)

• Dual blockage with Pertuzumab adds only a small benefit in Node + or ER negative disease.

• Lapatinib not useful. Neratinib too toxic and small benefit.

• T-DM1 role is post-neoadjuvant is interesting (but expensive!)

• Open questions:•Role of 2 anti-HER-2 agents alone (with no CT)?•Resistance•Biomarkers to decide for dual-blockade

• Expensive medicines are not the priority! Except TRASTUZUMAB, which is now an WHO essential medicine

• FOCUS ON:

• EARLY DETECTION / EDUCATION / AWARENESS

• MULTIDISCIPLINARY CARE

• QUALITY PATHOLOGY

• ACCESS TO RADIOTHERAPY (no RT – BCS very, very difficult)

• BIOSIMILARS and GENERICS (if approved and high-quality)

• FIGHT FOR TRASTUZUMAB

• FOCUS ON TAMOXIFEN, ANTHRACYCLINES, TAXANES

• ON’T WA TE RE OURCE on “fashionable things”

TAKE-HOME MESSAGES

Is the difference between the curves clinically significant?

89.8%

89.4%

DFS Absolute difference 0.4%

96.1%

95.7%

Invasive DFS Absolute difference 2.3%

PERSEPHONE

APHINITY

THANK YOU! OBRIGADA!

Breast Unit

BACK-UP

Superiority of (some) A-based regimens over CMF

WHICH TYPE OF CHEMOTHERAPY?


EBCTCG Overview – Anthracyclines versus CMFStandard strenght anthracycline–based regimen vs standard or near-standard CMF

Recurrence RR: 0.89 (P=0.003)

BC Mortalitiy RR: 0.80 (P=0.00001)

Overall mortality RR: 0.84

(P=0.0002)

Low strenght anthracycline–based regimen vs standard or near-standard CMF

Recurrence RR: 0.99 (P=0.76)

BC Mortalitiy RR: 0.98 (P=0.67)

Overall mortality RR: 0.97

(P=0.55)


Superiority of A & T-containing regimens over those A-based

WHICH TYPE OF CHEMOTHERAPY?Messages from the EBCTCG overview & individual trials

EBCTCG Overview – Taxane-plus-anthracycline versus anthracycline based regimenResults for all trials that test taxane effect (n = 44,000)

Distant Recurrence RR: 0.87Any recurrence RR:0,86, (P=0.00001)

BC Mortality RR: 0.87 (P=0.00001)Other mortality RR:0.99

Overall mortality RR: 0.89 (P=0.0001)

Unconfounded trials*(taxane vs control group)

8-y Recurrence: 30.2% vs 34.8% (absolute gain 4.6%)

8-y BC Mortality: 21.1% vs 23.9% (absolute gain 2.8%)

8-y Overall mortality 23.5% vs 26.7% (absolute gain 3.2%)

Counfounded trials*(taxane vs control group)

8-y Recurrence: 19.2% vs 22% (absolute gain 2.9%)

8-y BC Mortality: 10.1% vs 11.5% (absolute gain 1.4%)

8-y Overall mortality 11.2% vs 12.4% (absolute gain 1.2%)


Efficacy of Aromatase Inhibitors: Upfront

WHICH TYPE OF ENDOCRINE THERAPY?Messages from the EBCTCG overview & individual trials

Study Treatment arms/Population (n)

MedianFU


AIs 5 years ATAC TAM 5y vs ANA 5y

3116/ 3125120 months

HR= 0·91 (95% CI 0·83-0·99)p = 0·04

0.97 (95% CI 0.88–1.08)

p = 0·6BIG 1.98 TAM 5y vs LET 5y

2459/ 246376 months

HR=0·88 (95% CI 0·78–0·99)p = 0.03

HR 0.87 (95% CI 0.75-1.02)p = 0.08

TEAM EXE 5y vs TAM 2-3y followed EXE 2-3y4868/4898

5.1 y HR=0·97 (0·88–1·08)p=0·60

HR=1.00 (0·89–1·14)p>0.9

Meta-analysis

Cohort 1

AIs initial monotherapy vs TAM

9,856

5.8 y 9.6% AI v 12.6% TAM

2.9% absolute decrease (SE 0.7%)

2P <.00001

4.8% AI v 5.9% TAM

1.1% (SE =0.5%) absolute decrease

2P =0 .1MA.27 EXE 5y vs ANA 5y

7,5764.1y HR=1.02 ( 95% CI, 0.87 to

1.18)

P =0 .85

HR=0.93 ( 95% CI,0.77 -1.13)

P= 0 .46


Efficacy of Tam & Aromatase Inhibitors in Sequence

Study Treatment arms/ Population (n)

MedianFU


AIs and Tamoxifen in switching strategiesBIG 1.98 LET 5 y

TAM 2 y followed by LET 3 y

LET 2 y followed by TAM 3 y

1546/ 1548/ 1540

71 months

HR=1·05 (95% CI 0·84–1·32)HR=0·96 (95% CI 0·76–1·21)

HR=1.13 (95% CI 0·83–1·53)HR=0.90 (95% CI 0·65–1·24)

ABCSG-8/ARNO 95

TAM 5y vs Tam f 2y followed by ANA

for 3 years

28 months

HR=0·60 (0·44–0·81)p=0·0009

p=0·16

ITA TAM 5y vs Tam f 2y followed by ANA

128 months

HR=0·64 (0·44–0·94)p = 0.023

HR=0.72 (0·44–1.17)p = 0.3

IES TAM 5y vs Tam f 2-3y followed by EXE 2-3y

55·7 months

HR=0·76 (95% CI 0.66–0·88)p=0·0001

HR 0.·85 (95% CI 0·71–1·02)p=0·08

Meta-analysis

Cohort 2AIs T after 2-3 y of TAM vsTAM9,015

3.9y 5.0% AI v 8.1% TAM

3.1% absolute decrease (SE 0.6%)

2P <.00001

1.7% AI v 2.4% TAM

0.7% (SE =0.3%) absolute decrease

2P =0 .2


Efficacy of Extended Adjuvant Strategies


Study Treatment arms/Population (n)

MedianFU


ATLAS TAM 5y vs TAM 10y3428/ 3418

NR RR=0·90 (95% CI 0.79–1·02) 5-9yRR=0·75 (95% CI 0·62–0·90) laterRR 0·84, 95% CI 0·76–0·94;p=0·002in ER+

RR=0.97 (95% CI 0·79–1·18) 5–9 yRR= 0·71 (95% CI 0·58–0·88) later639 deaths vs 722 deaths, p=0·01 in ER+

NSABP-B14

TAM 5y vs TAM >5y579/ 593

7 y DFS = 82% TAM 5y vs 78% TAM >5y

p= .03

OS7Y = 94% TAM 5y vs 91% TAM >5y; p= .07

aTTOM TAM 5y vs TAM 10y6,934

4.2 y 415 vs 442 recurrencesRR=0.94 (95% CI 0.81–1.09); p=0.4

NA

MA.17 TAM 5y followed LET 5y vs TAM 5y2594/ 2593

30 ms HR= 0·58 (95% CI 0·45–0·76)p <.001

HR=0·82(95% CI 0·57–1.19)p =0.03

NSABP-

B33

TAM 5y followed EXE 5y vs TAM 5y

779/ 786

30 ms DFS 4y 91% v 89%RR=0·68 (p=0·07)

16 deaths vs 13 p =0.1

ABCSG-6a TAM 5y followed ANA 3y vs TAM 5y

469/ 387

62 ms HR= 0·62 (95% CI 0·40–0·96)p=0.031

HR= 0·89 (95% CI 0·59–1·34)p=0.57

current standards and practice changing studies in early ...€¦ · ihc translation of molecular...

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