Reach to Recovery International Conference 2019

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

Chair, ABC Global Alliance and ABC GuidelinesESMO Board of Directors & Director of Membership

ESO Breast Cancer Program Coordinator

The newest and most promising treatments

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

DISCLOSURES SLIDE

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, Tesaro, 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

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

The management of ABC is complex and, therefore, involvement of all appropriate specialties in a multidisciplinary team (including but not restricted to medical, radiation, surgical oncologists, imaging experts, pathologists, gynecologists, psycho-oncologists, social workers, nurses and palliative care

specialists), is crucial.(LoE/GoR: Expert opinion/A) (100%)

GENERAL RECOMMENDATIONS

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Annals of Surgery 2016

THE ROLE OF EXPERIENCE AND EXPERTISE

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

< 50 bcp vs > 150 bcp75% vs 84% survival at 5 years

CRUCIAL IMPORTANCE OF EXPERIENCE

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

BREAST CANCER MOLECULAR SUBTYPES

Courtesy of MJ Brito

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

MOLECULAR CLASSIFICATION OF BREAST CANCER - SURROGATES

Subtype Histological characteristicsSURROGATES

Biology/treatment

Luminal A • ER+• low grade/low proliferation

• indolent behaviour• sensitive to hormonal therapy

Luminal B • ER+ (lower expression than in luminal A)• high grade/high proliferation

• more aggressive behaviour than luminal A•less sensitive to hormonal therapy thanluminal A

Basal-like •“ Triple negative” (ER-, PR -, HER 2-)

• high grade/high proliferation

• aggressive behaviour• sensitive to chemotherapy

Her-2enriched

• HER 2+ • aggressive• sensitive to anti-HER-2 therapy• sensitive to chemotherapyRea

ch to

Rec

over

y Int

erna

tiona

l Con

fere

nce

2019

Nucleus

A tumor cell in the Seventies

?

Cytoplasm

Courtesy of T. Tursz

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

-cat

SOSGRB2

-cat

E-cad

HGF

GDNFMET EGFR

PTEN

NF2

?

? ? ?

E2FDP

P105-RBP

p16

CYC D1

CDK4

S-Phase genes

Tcf-4

-cat

WT1

p53 P21 Gene? Other targets ?

MLH1PMS2

MSH2GTBP(MSH3)

BRDCA2

BRCA1Rad51

Nucleus

?

ATM?

PI-3K

MAPKsCytoplasm

DNA mismatch

?

Hh

?

PTCH

SMO

Repair ?

RET

ELG-C

RNA Pol II

ELG-BVHL

-cat

? Target genes ?

? Target genes ?

EGF

GTP

APC

MEN1

NF1

RAS

RAF

Mdm-2

ELG-A

? Target genes ?

A tumor cell in the 2000’s

Courtesy of T. Tursz

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

THE 2 MAIN PROBLEMS IN ONCOLOGY TODAY

✓ PATIENT SELECTION

✓ TUMOR RESISTANCE

GENERAL RECOMMENDATIONSTREATMENT

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Treatment Treatment

Response Resistance Response

Progression

THE MAJOR PROBLEM OF TUMOR RESISTANCE TO THERAPY

J. Ribeiro & F. Cardoso

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

BIOPSY OF METASTATIC DISEASE

A biopsy (preferably providing histology) of a metastatic lesion should be performed, if easily accessible, to confirm diagnosis particularly when metastasis is diagnosed for the first time. (LoE/GoR: I/B) (98%)

Biological markers (especially HR and HER-2) should be reassessed at least once in the metastatic setting, if clinically feasible.(LoE/GoR: I/B) (98%)

Depending on the metastatic site (e.g. bone tissue), technical considerations need to be discussed with the pathologist.

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

SHOULD WE TREAT METASTATIC CANCER BASED ON THE BIOLOGY OF THE PRIMARY OR BIOPSY?

REASSESS BIOLOGY AT TIME OF RECURRENCE IS CRUCIAL

• Biology changes every time we give a new treatment

ONGOING EVALUATION OF DISEASE STATUS & BIOLOGY

But, SERIAL BIOPSIES are very difficultReach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

PET-CT

whole body CT

whole body MRI

LIQUID BIOPSIES

NANOTECHNOLOGY

PERFORM MINIMAL OR NON-INVASIVE SERIAL EVALUATIONS OF

DISEASE STATUS/BIOLOGY

IMAGING & FUNCTIONAL IMAGING

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

The “bomb”

Tumor cell in division

The “missiles”

Chemotherapy Endocrine Therapy Ant-HER-2 therapy

Tumor cell with hormonal receptors

(about 2/3 of BC)

Tumor cell with HER-2 receptors

(about 1/5 of BC)

THE « WEAPONS » OF MEDICAL ONCOLOGY

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

The newest and most promising treatments

for Metastatic/Advanced Breast Cancer

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

TREATMENT TAILORING IN ABC

Treatment choice should take into account at least these factors: HR & HER-2 status, previous therapies and their toxicities, disease-free interval, tumor burden (defined as number and site of metastases), biological age, performance status, co-morbidities (including organ

dysfunctions), menopausal status (for ET), need for a rapid disease/symptom control, socio-economic and psychological factors, available therapies in the patient’s country and patient preference.

(LoE/GoR: Expert opinion/A) (100%)Tailoring Therapy In Metastatic Breast Cancer

TAILOR FOR THE PATIENT TAILOR FOR THE DISEASEboth biologically and clinically

INDIVIDUALIZEDTREATMENT

Target

PATIENT PREFERENCES (Incurable setting; Quality & Quantity of Life)

PATIENT CHARACTERISTICS

DISEASE clinical CHARACTERISTICS

TUMOR CHARACTERISTICS (Biomarkers)

SEVERAL AVAILABLE OPTIONS FOR THE MANAGEMENT OF ER+/HER-2 neg ABC

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

ENDOCRINE THERAPY

1st example of TARGETED THERAPY

ER: estrogen

receptor

THE TARGETTHE LIGAND

Aromatase inhibitors

TamoxifenFulvestrantRea

ch to

Rec

over

y Int

erna

tiona

l Con

fere

nce

2019

Endocrine therapy (ET) is the preferred option for hormone receptor positive disease, even in the presence of visceral disease, unless there is visceral crisis or concern/proof of endocrine resistance.

(LoE/GoR: I/A) (93%)

ER POSITIVE / HER-2 NEGATIVE MBC

ALL guidelines are in agreement for this recommendationRea

ch to

Rec

over

y Int

erna

tiona

l Con

fere

nce

2019

ESMO Guidelines for the Use of First-Line Endocrine Therapy in Postmenopausal HR+ ABC

Image adapted from Senkus & Cardoso F, et al. Ann Oncol. 2013, ESMO GUIDELINES

ENDOCRINE TREATMENT STRATEGY

ET2response

ET3 ET…response responseET1

CT

MAIN RESEARCH QUESTION:OPTIMAL SEQUENCERea

ch to

Rec

over

y Int

erna

tiona

l Con

fere

nce

2019

Endocrine-Based Therapies for Breast

Cancer

Year Agent Mechanism

1977 SERMs

Tamoxifen

Toremifene

Antagonizes ER in breast tissue

1990s AIs

Anastrozole

Exemestane

Letrozole

Inhibit estrogen production in

postmenopausal women

2000s ERD

Fulvestrant

Impairs ER dimerization, increases ER

degradation, and disrupts nuclear localization

of ER

2010s Combinations

Exemestane/everolimus

Letrozole/palbociclib

Fulvestrant/palbociclib

Blockade of estrogen signaling and

prosurvival or cell cycle pathways

Slide credit: clinicaloptions.com

Lim E, et al. Oncology (Williston Park). 2012;26:688-694.

Croxtall JD, et al. Drugs. 2011;71:363-380.

Vidula N, et al. Clin Breast Cancer. 2016;16:8-17.

Mustonen MV, et al. World J Clin Oncol. 2014;5:393-405.

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

http://www.clinicaloptions.com/oncology

The preferred 1st line ET depends on type and duration of adjuvant ET as well as time elapsed from the end of adjuvant ET; it can be an aromatase inhibitor, tamoxifen or fulvestrant.


ER POSITIVE / HER-2 NEGATIVE MBC

* for pre and peri- with OFS/OFA, men (preferably with LHRH agonist) and post-menopausal womenRea

ch to

Rec

over

y Int

erna

tiona

l Con

fere

nce

2019

Estrogen

Cell

growth

Estrogen

receptor

Aromatase Inhibitors

ER & GROWTH FACTOR PATHWAYS & ENDOCRINE RESISTANCE

Cytoplasm

Nucleus

LBD

LBD

Cofactor complex

AF1 DBD

DBDAF1

SOS

(EG

FR

ShcRAS

RAF PI3K

Akt

m-TOR

MEK

HE

R2

P

P P

MAPK

Growth factor

receptor

GRB2

HDAC inhibitors (Entinostat)

Adapted from Denise Yardley et al, ASCO-Breast 2011

M-TOR inhibitor(Everolimus,

Sirolimus)

Tamoxifen

Anti-HER-2 agents

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Cell cycle CDKs

CDK 4/6 INHIBITORS (Palbociclib, Ribociclib, Abemaciclib)

They delay ET resistance by regulating the cell cycle (i.e. the cell clock)

Courtesy B. Sousa

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

http://www.google.pt/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&docid=lB_jAIRrVIqm_M&tbnid=g4jVLSTbeKwL0M:&ved=0CAUQjRw&url=http://www.preciolandia.com/br/relogio-automatico-modelos-esqueleto-maq-79u5tn-a.html&ei=qbKFU6TFG5Oh7AafqIHIAQ&bvm=bv.67720277,d.d2k&psig=AFQjCNGvAVigOnfa8n6-98tXJ_uRt73OEw&ust=1401357273492295

PFS: Investigator-Assessed - (ITT Population)

ITT=intent-to-treat; LET=letrozole; NR=not reached; PAL=palbociclib; PCB=placebo; PFS=progression-free survival.

0 3 6 9 12 15 18 21 24 27 30 33

Time (Month)

0

10

20

30

40

50

60

70

80

90

100

Pro

gre

ssio

n-F

ree

Su

rviv

al P

rob

abili

ty (

%)

444 395 360 328 295 263 238 154 69 29 10 2PAL+LET222 171 148 131 116 98 81 54 22 12 4 2PCB+LET

Number of patients at risk

Pro

gre

ss

ion

-Fre

e S

urv

iva

l, %

Time, months

PAL+LET

(N=444)

PCB+LET

(N=222)

Number of Events, n (%) 194 (44) 137 (62)

Median (95% CI) PFS 24.8 (22.1–NR) 14.5 (12.9–17.1)

HR (95% CI); 1-sided P value 0.58 (0.46–0.72); P<0.000001

PALOMA-2

Hortobagyi et al, ESMO 2016, updated ASCO 2017NEJM 2017

PFS (Investigator Assessment)

Ribociclib + Letn=334

Placebo + Letn=334

Number of events, n (%) 93 (28) 150 (45)

Median PFS, months (95% CI)

NR(19.3–NR)

14.7 (13.0–16.5)

Hazard ratio (95% CI) 0.556 (0.429–0.720)

One-sided p value 0.00000329

MONALEESA 2: PRIMARY ENDPOINT WAS MET EARLY

◆ PFS results by independent central review: hazard ratio 0.592 (95% CI: 0.412–0.852; p=0.002)

No. of patients at risk

Ribociclib + Let 334 294 277 257 240 226 164 119 68 20 6 1 0

Placebo + Let 334 279 264 237 217 192 143 88 44 23 5 0 0

Pro

bab

ility

of

Pro

gre

ssio

n-f

ree

Su

rviv

al (

%)

0

20

40

60

80

100

0 4 8 12 16 20 24 Time (months)

Let, letrozole; NR, not reached.

Monaleesa 2 - Updated results ASCO 2017

Median PFS

abemaciclib + NSAI: not reached

placebo + NSAI: 14.7 months

HR (95% CI): 0.543 (0.409, 0.723)

p = 0.000021

PFS benefit confirmed by blinded independent central review: HR (95% CI): 0.508 (0.359, 0.723); p = 0.000102

MONARCH 3: Primary Endpoint: PFS (ITT)

Di Leo et al, ESMO 2017

1st Line CDK 4/6 INHIBITORS: EFFICACY

MONALEESA-7: RESULTS

CI, confidence interval; NR, not reached.1. Tripathy D et al. SABCS 2017;abst GS2-05 (oral); 2. Tripathy D et al. Lancet Oncol 2018;19:904–915.

MONALEESA-7:

• Ribociclib + ET reduced

the risk of progression by

45% vs the placebo arm

(p<0.0001)1,2

• Manageable safety profile

consistent with prior

studies of ribociclib1,2

Pro

bab

ilit

y o

f P

FS

(%

)

Time (months)

335 301 284 264 245 235 219 178 136 90 54 40 20 3 1 0

337 273 248 230 207 183 165 124 94 62 31 24 13 3 1 0

1086420

100

80

60

40

20

0

30282624222018161412

10

30

50

70

90

Placebo + ET

Ribociclib + ET

No. at risk

Placebo + ETRibociclib + ET

PFS (investigator assessed)1,2

Ribociclib + ETN=335

Placebo + ETN=337

Median PFS, months (95% CI) 23.8 (19.2–NR) 13.0 (11.0–16.4)

Hazard ratio (95% CI) 0.55 (0.44–0.69), p<0.0001

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Initial QoL Presentation: no difference in QoL!

HR QoL Monaleesa 2 (no significant differences)

Change From Baseline in Global Health Patient-reported

Outcomes, by Treatment Arm –EORTC QLQ-C30

Questionnaire

Time to definitive deterioration of the global health

status/QoL scale score of the EORTC QLQ-C30

questionnaire by at least 10%

Verma et al. ASCO 2017

Abemaciclib: no QoL yet reported

1st Line CDK 4/6 INHIBITORS: IMPACT ON QoL

TTD ≥10% IN GLOBAL HRQoL WAS DELAYED

WITH RIBOCICLIB VS PLACEBO

aPatients censored at progression; bSimilar results obtained with TTD ≥5%, ≥10%, and ≥15%.

No. at risk

Ribociclib + ET 335 282 256 236 218 201 188 145 112 69 43 41 15 3 0

Placebo + ET 337 260 218 198 178 158 132 97 67 38 18 17 6 1 0

Ribociclib + ET

N=335

Placebo + ET

N=337

No. of events 102 115

Months, median

(95% CI)

NR

(22.2–NR)

21.2

(15.4, 23.0)

Hazard ratio (95% CI) 0.70 (0.53–0.92), p=0.004

TTD ≥10% in global health status/QoL score of EORTC QLQ-C30a,b

Eve

nt-

free

pro

bab

ilit

y (%

)

100

80

60

40

20

0

Time (months)

0 2 4 6 8 10 12 14 16 18 20 22 24 2826

Placebo + ETRibociclib + ET

N. Harbeck et al, ESMO 2018Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

MONALEESA-7 Study Design

Stratification Factors• Liver/lung metastasis (yes/no)• Prior chemotherapy (yes/no)• Combination partner (NSAI/TAM)

Primary endpoint

•PFS (local)

Key secondary endpoint

•OS

Select secondary endpoints

•HRQOL

•ORR

•TTDD of ECOG PS

•Safety

Pre/perimenopausal

womena with

HR+/HER2− ABC

No prior ET for ABCb

≤ 1 prior CT for ABC

N = 672

Ribociclib

600 mg/day;

3 weeks on/1 week off

+

NSAI/TAMc + GOSd

n = 335

Placebo

3 weeks on/1 week off

+

NSAI/TAMc + GOSd

n = 337

ANA, anastrozole; CT, chemotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; FSH, follicle-stimulating hormone; GOS, goserelin; HRQOL, health-related quality of life; NSAI, nonsteroidal aromatase inhibitor; ORR, objective response rate; TAM, tamoxifen; TTDD, time to definitive deterioration.a Premenopausal status was defined as either patient had last menstrual period ≤ 12 months or if receiving TAM or toremifene for ≤ 14 days, plasma estradiol and FSH must be in normal premenopausal range or in the case of induced amenorrhea, plasma estradiol and FSH must be in normal premenopausal range. Perimenopausal status was defined as neither premenopausal nor postmenopausal (prior bilateral oophorectomy, age ≥ 60 years, or FSH and plasma estradiol levels in normal postmenopausal range). Patients could not be ≥ 60 years of age. b

Patients who received ≤ 14 days of NSAI/TAM ± GOS were allowed. c TAM and NSAI were administered daily orally. TAM dose was 20 mg, LET dose was 2.5 mg. and ANA dose was 1 mg. d GOS 3.6 mg was administered by subcutaneous injection.

First Phase III trial with a CDK4/6 inhibitor exclusively in premenopausal patients

Dr Sara Hurvitz

Ran

do

miz

ed

1:1

S. Hurvitz, ASCO 2019

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Overall Survival

3

5

Dr Sara Hurvitz

Ribociclib + ET Placebo + ET

Events/N 83/335 109/337

Median OS, mo Not reached 40.9

HR (95% CI) 0.712 (0.535-0.948)

P value .00973

Kaplan-Meier

Estimate

Ribociclib +

ETPlacebo + ET

36 months 71.9% 64.9%

42 months 70.2% 46.0%

• ≈ 29% relative reduction in risk of death

Landmark Analysis

S. Hurvitz, ASCO 2019

RIBOCICLIB 1st line Pre-menopausal:

MCBS: 5

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

2nd Line CDK 4/6 INHIBITORS: EFFICACY

0 2 4 6 8 10 12 14 16 18 20 22Time (Month)

0

10

20

30

40

50

60

70

80

90

100

Pro

gre

ss

ion

-Fre

e S

urv

ival

Pro

bab

ilit

y (

%)

Palbociclib+Fulvestrant (N=347) Median PFS=11.2 months 95% CI (9.5, 12.9)Placebo+Fulvestrant (N=174) Median PFS=4.6 months 95% CI (3.5, 5.6)

HR=0.49795% CI (0.398, 0.620)1-sided p<0.000001

347 276 245 215 189 168 137 69 38 12 2 1PAL+FUL174 112 83 62 51 43 29 15 11 4 1PBO+FUL


FINAL PROGRESSION-FREE SURVIVAL IN PALOMA-3 (ITT)1

38

FUL=fulvestrant; HR=hazard ratio; ITT=intent-to-treat; PAL=palbociclib; PBO=placebo.

1. Ibrance Summary of Product Characteristics; Pfizer Ltd; Kent, UK; 2018. Data cutoff date: 23 October 2015.

Absolute improvement in median PFS was 6.6 months

Cristofanilli et al, ESMO 2018

MONARCH 2: Primary Endpoint: PFS (ITT)

Median PFS

abemaciclib + fulvestrant: 16.4 months

placebo + fulvestrant: 9.3 months

HR (95% CI): .553 (.449, .681)

P < .0000001

PFS benefit confirmed by blinded independent central review (HR: .460; 95% CI: .363, .584; P < .000001)

Courtesy G. Sledge et al

• Ribociclib + fulvestrant

reduced the risk of

progression by 41% vs

placebo + fulvestrant

(p<0.001)1,2

No. at risk

Ribociclib + fulvestrant

Placebo + fulvestrant

484

242

403

195

365

168

347

156

324

144

305

134

282

116

259

106

235

95

155

53

78

27

52

14

13

4

0

0

Time (months)

Pro

bab

ilit

y o

f P

FS

(%

)

100

80

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26

MONALEESA-3: FINAL PFS

CI, confidence interval; HR, hazard ratio.aInvestigator assessed.

1. Slamon DJ et al. ASCO 2018;abst 1000 (oral); 2. Slamon DJ et al. J Clin Oncol 2018;36:2465–2472.

PFSa,1,2 Ribociclib + fulvestrantN=484

Placebo + fulvestrantN=242

Median PFS, months (95% CI)

20.5 (18.5–23.5)

12.8 (10.9–16.3)

HR (95% CI) 0.59 (0.48–0.73), p<0.001

P. Fasching, ESMO 2018

aNo prior endocrine therapy for ABC;bUp to one line of prior endocrine therapy for ABC or relapse on/within 12 months of (neo)adjuvant endocrine therapy; cInvestigator assessed.

1. Slamon DJ et al. ASCO 2018;abst 1000 (oral); 2. Slamon DJ et al. J Clin Oncol 2018;36:2465–2472.

PFS BENEFIT CONSISTENT ACROSS TREATMENT SETTINGS

First linea Second line +

early relapseb

238

129

205

109

189

99

180

91

173

88

166

85

159

78

149

75

141

68

97

40

49

18

31

10

7

4

0

0

236

109

188

83

167

67

159

63

143

54

132

47

117

36

104

29

91

25

55

12

28

8

20

4

5

0

0

0

Pro

bab

ilit

y o

f P

FS

(%

)

26181614121086420 20 22 24

0

20

40

60

80

100

Time (months)

Pro

bab

ilit

y o

f P

FS

(%

)

26222016121086420 1814 24

0

20

40

60

80

100

Time (months)No. at risk



No. at risk



PFSc,1,2

Ribociclib +fulvestrant

n=238


n=129Median PFS, months

NR 18.3

HR (95% CI) 0.58 (0.42–0.80)

PFSc,1,2

Ribociclib +fulvestrant

n=236


n=109Median PFS, months

14.6 9.1

HR (95% CI) 0.57 (0.43–0.74)

P. Fasching, ESMO 2018Rea

ch to

Rec

over

y Int

erna

tiona

l Con

fere

nce

2019

OVERALL SURVIVAL IN PALOMA-3 (ITT)

Absolute improvement in median OS was 6.9 months

BUT

NOT STATISTICALLY SIGNIFICANT

0 6 12 18 24 30 36 42 48 54

Time (Months)

0

10

20

30

40

50

60

70

80

90

100O

ve

rall

Su

rviv

al

Pro

ba

bilit

y (

%)

Palbociclib+Fulvestrant (N=347)

Median OS=34.9 months

95% CI (28.8–40.0)

Placebo+Fulvestrant (N=174)

Median OS=28.0 months

95% CI (23.6–34.6)

Stratified HR=0.81

95% CI (0.64–1.03)

1-sided P=0.043

Unstratified HR=0.79

95% CI (0.63–1.00)

1-sided P=0.025

347 321 286 247 209 165 148 126 17PAL+FUL

174 155 135 115 86 68 57 43 7PBO+FUL


Cristofanilli et al, ESMO 2018

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Abemaciclib: no QoL yet reported

2nd Line CDK 4/6 INHIBITORS: IMPACT ON QoL

PALOMA 3: Impact on Global QOL, Functioning and Symptoms

Time to Deterioration¥ in Pain Scores (QLQ-C30)

Conclusions

Compared to placebo + fulvestrant, addition of palbociclib to fulvestrant in endocrine resistant HR+/HER2– MBC patients was associated with:

❖ Significantly higher on treatment overall Global QOL scores

❖ Significantly greater improvement from baseline in emotional functioning and pain scores

❖ Significant delay in deterioration of pain

ECCO 2015: Harbeck et al

*Deterioration

defined as a ≥10-

point increase from

baseline.

+Censored.

Median: Palbociclib + Fulvestrant (8 mo) vs Placebo + Fulvestrant (2.8 mo); HR=0.642: P< 0.001

TTD ≥10% in global health status/QoL score of EORTC QLQ-C30a

GLOBAL HRQoL

NR, not reached.aPatients censored at progression.


N=484


N=242

No. of events, n (%) 139 (28.7) 79 (32.6)

Months, median

(95% CI)

NR

(22.1–NR)

19.4

(16.6–NR)

HR (95% CI) 0.80 (0.60–1.05)

No. at risk

Ribociclib + fulvestrant 351 308 286 264 251 228 205 177 105 56 49 10 0

Placebo + fulvestrant 175 150 142 123 108 97 81 69 40 18 18 3 0

Eve

nt-

free

pro

bab

ilit

y (%

)

100

80

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Time (months)

Placebo + fulvestrantRibociclib + fulvestrant

484

242


Ribociclib + fulvestrant, n 361 316 300 283 251 240 218 216 185

Placebo + fulvestrant, n 169 149 133 133 116 105 96 84 82

LS mean SEM

GLOBAL HRQoL IMPROVED/MAINTAINED VS

BASELINE WHILE ON TREATMENT IN BOTH ARMS

C, cycle; D, day; LS, least squares; S, screening; SEM, standard error of the mean.aEOT assessment occurred within 15 days from last dose of study drug.

8

4

0

–4

–8

C3D1 C5D1 C7D1 C9D1 C11D1 C13D1 C15D1 C17D1 C19D1 EOT

Time point

Placebo + fulvestrantRibociclib + fulvestrant

Change from baseline in global health status/QoL score of EORTC QLQ-C30

S/ /

184

113

Ch

ang

e fr

om

bas

elin

e

HRQoL

declines

at EOTa


QoL similar in both armsReach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

10 MONTHS BENEFIT IN PFS 1st lineOS BENEFIT 1st line in Pre-menopausal6 MONTHS BENEFIT IN PFS in 2nd line

COST: 5.000 €/cycle

CDK 4/6 INHIBITORS (Palbociclib, Ribociclib, Abemaciclib)

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Everolimus (mTOR inhibitor)

PI3K

AKT

PTEN

mTOR

RAS

RAF

MEK

MAPK

ER target gene transcription

P P

EGFRHER2

E

E

ER

E

ER

E

ER

E

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

4.6 to 6.9 ms benefit PFS

BOLERO-2 (18-ms FU): PFS Central

2

EVE 10 mg + EXE

PBO + EXE

Number of patients still at risk

HR = 0.38 (95% CI: 0.31-0.48)

Log-rank P value: <.0001

Kaplan-Meier medians

EVE 10 mg + EXE: 11.0 months

PBO + EXE: 4.1 months

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108

485

239

427

179

359

114

292

76

239

56

211

39

166

31

140

27

108

16

77

13

62

9

48

6

32

4

21

1

18

0

11

0

10

0

5

0

0

0

Censoring times

EVE 10 mg + EXE (n/N = 188/485)

PBO + EXE (n/N = 132/239)0

20

40

60

80

100

Pro

bab

ilit

y (

%)

of

Ev

en

t

Time (week)

Piccart M, et al. ASCO 2012. Abstract 559.

BOLERO-2 (39-mo): Final OS Analysis

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50

Pro

bab

ilit

y o

f O

vera

ll S

urv

ival

Time, months

EVE+EXE (n/N = 267/485)

PBO+EXE (n/N = 143/239)

232

109

248

113

266

120

279

130

292

145

311

153

330

162

347

170

373

182

399

194

414

201

429

211

448

220

471

232

485

239

EVE+EXE

PBO+EXE

No. at risk

HR = 0.89 (95% CI, 0.73-1.10)Log-rank P = .14

Kaplan-Meier mediansEVE+EXE: 30.98 monthsPBO+EXE: 26.55 months

Censoring times

11

5

23

8

39

18

58

28

91

41

118

56

154

77

196

98

216

102

0

0

1

1

• At 39 months median follow-up, 410 deaths had occurred (data cutoff date: 03 October 2013): 55% deaths (n = 267) in the EVE+EXE arm vs 60% deaths (n = 143) in the PBO+EXE arm

Piccart M, et al, EBCC 2014,LBA

Everolimus + AI

4 months “absolute benefit” in OSBUT

NOT STATISTICAL SIGNIFICANT

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Management of MUCOSITIS/STOMATITIS

Steroid mouthwash should be used for prevention of stomatitis induced by mTOR inhibitors (suggested schedule: 0.5mg/5ml dexamethasone,

10 ml to swish x 2 minutes then spit out qid). (LoE/GoR: I/B)

Early intervention is recommended. For > Grade 2 stomatitis, delaying treatment until the toxicity resolves and considering lowering the dose of the targeted agent are also recommended. Mild toothpaste and gentle hygiene are recommended for the treatment of stomatitis. Consider adding steroid dental paste to treat developing ulcerations.(LoE/GoR: Expert opinion/B).

Probably today MCBS = 3

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

6 MONTHS BENEFIT IN PFS in 2nd lineNO OS BENEFIT SEEN

COST: 3.500 €/cycle

Everolimus

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

NEW DRUGS ARRIVING . . .

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

PI3K

PTEN

PDK

1

Subtype HR+ HER2- TNBC

PIK3CA mut 40% 7-9%

PTEN mut/loss 2-4% 30-40%

PIK3R1 mut 3% 1%

AKT1 mut 2-3% Rare

Modified from Ma et al, Nat Rev Cancer 2015; ASCO 2018

Courtesy R. Dent, ESMO 2018

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

European Society for Medical Oncology, 19–23 October, 2018, Munich, Germany

This presentation is the intellectual property of Fabrice Andre.

Contact [email protected] for permission to reprint and/or distribute.

SOLAR-1 (NCT02437318, Alpelisib) Primary endpoint:

Locally assessed PFS in the PIK3CA-mutant cohort

Data cut-off:

Jun 12, 2018

Alpelisib +

fulvestrant

(N=169)

Placebo +

fulvestrant

(N=172)

Number of PFS

events, n (%)103 (60.9) 129 (75.0)

Progressio

n99 (58.6) 120 (69.8)

Death 4 (2.4) 9 (5.2)

Censored 66 (39.1) 43 (25.0)

Median PFS

(95% CI)

11.0

(7.5–14.5)

5.7

(3.7–7.4)

HR (95% CI) 0.65 (0.50–0.85)

p-value 0.00065

• The primary endpoint crossed the

pre-specified Haybittle-Peto boundary

(one-sided p≤0.0199)

F. André et al, ESMO 2018




SOLAR 1

Adverse events in the total population*

*Safety profiles were similar in the PIK3CA-mutant and PIK3CA-non-mutant cohorts

AEs ≥20% in either arm, %

Alpelisib + fulvestrant

N=284


N=287

All Grade 3 Grade 4 All Grade 3 Grade 4

Any adverse event 282 (99.3) 183 (64.4) 33 (11.6) 264 (92.0) 87 (30.3) 15 (5.2)

Hyperglycemia 181 (63.7) 93 (32.7) 11 (3.9) 28 (9.8) 1 (0.3) 1 (0.3)

Diarrhea 164 (57.7) 19 (6.7) 0 45 (15.7) 1 (0.3) 0

Nausea 127 (44.7) 7 (2.5) 0 64 (22.3) 1 (0.3) 0

Decreased appetite 101 (35.6) 2 (0.7) 0 30 (10.5) 1 (0.3) 0

Rash 101 (35.6) 28 (9.9) 0 17 (5.9) 1 (0.3) 0

Vomiting 77 (27.1) 2 (0.7) 0 28 (9.8) 1 (0.3) 0

Decreased weight 76 (26.8) 11 (3.9) 0 6 (2.1) 0 0

Stomatitis 70 (24.6) 7 (2.5) 0 18 (6.3) 0 0

Fatigue 69 (24.3) 10 (3.5) 0 49 (17.1) 3 (1.0) 0

Asthenia 58 (20.4) 5 (1.8) 0 37 (12.9) 0 0

• Eighteen patients (6.3%) discontinued alpelisib due to hyperglycemia and 9 patients (3.2%) discontinued alpelisib

due to rash; no patients discontinued placebo due to either hyperglycemia or rash





SOLAR 1

Treatment exposure and dose adjustments

*The data cut-off for both groups was June 12, 2018.†1 patient in the placebo arm of the PIK3CA-mutant cohort did not receive fulvestrant or placebo.

Treatment exposure

PIK3CA-mutant* PIK3CA-non-mutant*


(N=169)

Placebo + fulvestrant(N=171)†


(N=115)


(N=116)

Exposure to alpelisib/placebo

Median duration of exposure to

alpelisib/placebo, months (range) [n exposed]5.5 (0.0–29.0) [168] 4.6 (0.0–30.1) [170] 5.6 (0.3–30.8) [115] 6.2 (0.5–29.5) [116]

Median relative alpelisib/placebo dose intensity,

%82.7 100 84.5 100

Alpelisib/placebo dose adjustments, n (%)

Patients with dose interruptions 125 (74.0) 55 (32.2) 80 (69.6) 31 (26.7)

Dose interruptions due to AEs 116 (68.6) 27 (15.8) 73 (63.5) 13 (11.2)

Patients with dose reductions 108 (63.9) 15 (8.8) 60 (52.2) 6 (5.2)

Dose reductions due to AEs 105 (62.1) 8 (4.7) 59 (51.3) 5 (4.3)


PI3K inhibitorsALPELISIB

6 Months benefit PFS

Only ~ 7% pretreated with CDK 4/6i

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

How do HDAC inhibitors work?We can re-write our epigenetic code via writers, erasers and readers

HDACi can reprogram the carcinogenic epigenetic changes

Courtesy R. Dent, ESMO 2018

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

HDAC inhibitorsChidamide?Entinostat?

4 Months benefit PFS

Not pretreated with CDK 4/6i

ACE (Chidamide) Trial: PFS in ITT Population

T i m e ( M o n t h s )

Pro

ba

bil

ity

of

Pro

gre

ss

ion

-fre

e S

urv

iva

l (%

)

0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 2 6 2 8 3 0

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

C h i d a m i d e + E x e m e s t a n e ( N = 2 4 4 )

M e d i a n p r o g r e s s - f r e e s u r v i v a l , 7 . 4 m o ( 9 5 % C I , 5 . 5 – 9 . 2 )

P l a c e b o + E x e m e s t a n e ( N = 1 2 1 )

M e d i a n p r o g r e s s - f r e e s u r v i v a l , 3 . 8 m o ( 9 5 % C I , 3 . 7 – 5 . 5 )

H a r z a r d R a t i o , 0 . 7 5 ( 9 5 % C I , 0 . 5 8 – 0 . 9 8 ) , P < 0 . 0 5

N o . a t R i s k

P l a c e b o + E x e m e s t a n e 1 2 1 7 6 5 4 4 3 3 8 2 7 1 9 1 4 8 2 2 1 1 0 0 0

C h i d a m i d e + E x e m e s t a n e 2 4 4 1 7 6 1 3 8 1 1 0 8 2 6 3 4 9 3 7 2 4 1 3 8 5 1 1 1 0

Z. Jiang et al, ESMO 2018

Non-hematologic Adverse Events

AEs > 20% in either arm, n (%)

Chidamide + Exemestane

(N=244)

Placebo + Exemestane

(N=121)


Hypokalemia 62 (25.4) 14 (5.7) 1 (0.4) 3 (2.5) 1 (0.8) 0

Nausea 61 (25.0) 1 (0.4) 0 7 (5.8) 0 0

Hyperglycemia 60 (24.6) 5 (2.1) 0 17 (14.1) 0 0

Hypocalcemia 58 (23.8) 2 (0.8) 0 3 (2.5) 0 0

Hypertriglyceridemia 57 (23.3) 10 (4.1) 2 (0.8) 15 (12.4) 0 0

Diarrhea 53 (21.7) 4 (1.6) 0 9 (7.4) 0 0

Aspartate aminotransferase increased 50 (20.5) 0 0 24 (19.8) 4 (3.3) 0

Alanine aminotransferase increased 49 (20.1) 0 0 20 (16.5) 2 (1.7) 0

Hematologic Adverse Events

AEs > 10% in either arm, n (%)

Chidamide + Exemestane

(N=244)

Placebo + Exemestane

(N=121)


Neutropenia# 199 (81.6) 102 (41.8) 22 (9.0) 31 (25.6) 1 (0.8) 2 (1.7)

Leukopenia 194 (79.5) 45 (18.4) 1 (0.4) 31 (25.6) 1 (0.8) 2 (1.7)

Thrombocytopenia 183 (75.0) 61 (25.0) 6 (2.5) 16 (13.2) 1 (0.8) 2 (1.7)

Anemia 78 (32.0) 9 (3.7) 0 22 (18.2) 2 (1.7) 0

#No febrile neutropenia was reported

Z. Jiang et al, ESMO 2018

ACE Study (Chidamide, HDAC inhibitor)

Phase III E2112: Exemestane ± Entinostat

in Advanced Breast Cancer

▪ Entinostat: oral, histone deacetylase inhibitor

▪ Primary endpoints: OS, PFS

▪ Secondary endpoints: ORR (CR or PR), TTD, toxicity

▪ Other outcomes: adherence, QoL, protein lysine acetylation

Pre/peri/postmenopausal

women and men with

HR+/HER2-, inoperable,

locally advanced or

metastatic BC, with

progression on/after NSAI

therapy

(N ≈ 600)

Entinostat PO Days 1, 8, 15, 22 +

Exemestane PO QD Days 1-28

(n ≈ 300)

Placebo PO Days 1, 8, 15, 22 +

Exemestane PO QD Days 1-28

(n ≈ 300)

Slide credit: clinicaloptions.comClinicalTrials.gov. NCT02115282.

Until disease

progression or

unacceptable

toxicity

*Pre/perimenopausal female and all male pts receive goserelin acetate SC Day 1.

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Cell

membrane

Ligand

binding

Activated receptor

Tumor Growth and

Metastases

Proliferation MigrationSurvival

Signal

transmition

HER-2 receptor TRASTUZUMAB

STOP

2nd EXAMPLE OF TARGETED THERAPY:

HER-2 RECEPTOR & TRASTUZUMAB

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

• Longer OS: 25.1 vs. 20.3 ms (p=0.046)

• Longer TTP: 7.4 vs. 4.6 ms (p0.001)

• Higher RR: 50 vs. 32% (p0.001)

• Longer duration: 9.1 vs. 6.1 ms (p0.001)

MCBS: 5Rea

ch to

Rec

over

y Int

erna

tiona

l Con

fere

nce

2019

HER2 receptor

Trastuzumab

Pertuzumab

Subdomain IV of HER2

Dimerisation domain of HER2

DUAL BLOCKADE: TRANSTUZUMAB + PERTUZUMAB

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

PI3K/Akt pathway

MAPK pathway

(Ras/Raf/

MEK/ERK)

Ligands

ErbB2Other ErbB

Proliferation Cell cycle, Survival

PI3K/Akt pathway

MAPK pathway

(Ras/Raf/

MEK/ERK)

Lapatinib

Lapatinib: TKI, small molecule, acts in the

intracellular domain

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Receptor-T-DM1 complex is internalized into HER2-positive cancer cell

Potent antimicrotubule agent is released once inside the HER2-positivetumor cell

T-DM1 binds to the HER2 protein on cancer cells

HER2

Trastuzumab-DM1

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

HER-2 POSITIVE ABC: 1st line

CT + trastuzumab and pertuzumabor

CT + trastuzumabor

ET + trastuzumab +/- pertuzumab or lapatinib

HER-2 POSITIVE ABC: 2nd line and beyond

T-DM1or

CT + trastuzumabor

ET + trastuzumabReach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

TRASTUZUMAB:COST: 2.200 €/cycle

ANTI-HER2 THERAPIES

PERTUZUMAB:COST: 6.500 €/cycle

OS SURVIVAL BENEFIT IN ALL LINES

TDM-1:COST: 4.000 €/cycle

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

NEW DRUGS ARRIVING . . .

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Hope S. Rugo, MD

Abstract #1000

1. Nordstrom JL, et al. Breast Cancer Res. 2011;13(6):R123. 2. Stavenhagen JB, et al. Cancer Res. 2007;67(18):8882-8890.

Margetuximab: Fc-engineered to Activate Immune Responses

Fab: •Same specificity and affinity•Similarly disrupts signaling

Fc engineering:•↑ Affinity for activating FcgRIIIA

(CD16A)•↓ Affinity for inhibitory FcgRIIB (CD32B)

Margetuximab1,2

Fab:•Binds HER2 with high specificity•Disrupts signaling that drives

cell proliferation and survival

Trastuzumab

Fc:•Wild-type immunoglobulin G1 (IgG1)

immune effector domains•Binds and activates immune cells

Margetuximab Binding to FcγR Variants:

Receptor Type Receptor

Allelic Variant

Relative Fc Binding

Affinity Fold-Change

Activating

CD16A158F Lower 6.6x ↑

158V Higher 4.7x ↑

CD32A131R Lower 6.1x ↓

131H Higher ↔

Inhibitory CD32B 232I/T Equivalent 8.4x ↓

H. Rugo, ASCO 2019

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Hope S. Rugo, MD

Abstract #1000

Arm 1

Margetuximab (15 mg/kg Q3W) + chemotherapy

in 3-week cycles

HER2+ advanced breast cancer

• ≥2 prior anti-HER2 therapies, including pertuzumab

• 1-3 prior treatment linesin metastatic setting

• Prior brain metastasis ok if treated and stable

Study CP-MGAH22-04 (SOPHIA) Design1,2

Stratification:• Chemotherapy choice• Prior therapies (≤2 vs >2)• Metastatic sites (≤2 vs

>2)

HR=hazard ratio; CBA=central blinded analysis.

1. Rugo HS, et al. J Clin Oncol. 2016;34(suppl 15):TPS630. 2. Clinicaltrials.gov. NCT02492711. www.clinicaltrials.gov/ct2/show/NCT02492711. Accessed April 8, 2019.

Investigator’s choice of

chemotherapy

(capecitabine, eribulin,

gemcitabine, or vinorelbine)

Sequential Primary Endpoints

• PFS (by CBA; n=257; HR=0.67; α=0.05; power=90%)• OS (n=385; HR=0.75; α=0.05; power=80%)

Secondary Endpoints • PFS (Investigator assessed)• Objective response rate (by CBA)

Tertiary/Exploratory Endpoints

• Clinical benefit rate (CBR), duration of response (DoR)• Safety profile, antidrug antibody• Effect of CD16A, CD32A, and CD32B on margetuximab

efficacy

Arm 2

Trastuzumab(8 mg/kg loading → 6 mg/kg Q3W)

+ chemotherapy

in 3-week cycles

1:1 Randomization

(N=536)

H. Rugo, ASCO 2019

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Hope S. Rugo, MD

Abstract #1000

SOPHIA TRIAL: PFS Analysis in ITT Population

24% Risk Reduction of Disease ProgressionCentral Blinded Analysis (Primary Endpoint)

• PFS analysis was triggered by last randomization on October 10, 2018, after 265 PFS events occurred

ITT population: N=536. CI=confidence interval.

Margetuximab + Chemotherapy

(n=266)

Trastuzumab + Chemotherapy

(n=270)

# of events 130 135

Median PFS (95% CI)

5.8 months (5.52–6.97)

4.9 months (4.17–5.59)

HR by stratified Cox model, 0.76(95% CI, 0.59–0.98)

Stratified log-rank P=0.033

H. Rugo, ASCO 2019Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

DS-8201a: a HER2-targeting Antibody-drug Conjugate

• DS-8201 is a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker

• Designed to deliver CT inside cancer cells and reduce systemic exposure in comparison to traditional CT

• Activity in HER2+ and “HER2 low”

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

TM

K

Overall survival according to subtype

Fietz, T., Tesch, H., Rauh, J., Boller, E., Kruggel, L., Jänicke, M., Marschner, N., 2017. Palliative systemic

therapy and overall survival of 1,395 patients with advanced breast cancer – Results from the prospective

German TMK cohort study. The Breast 34, 122–130, 2017

Prospective German TMK cohort study

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Heterogeneity of TRIPLE NEGATIVE BC: TNBC Classification

Le Du F. Oncotarget. 2015;6:12890-12908. This work is licensed under a Creative Commons

Attribution 3.0 Unreported License.Slide credit: clinicaloptions.com

Basal-like (BL)

TNBC

Mesenchymal-like TNBC

(ML-TNBC)Immune-associated

(IM) TNBC

Luminal/apocrine (LA) TNBC

HER2-enriched (HER2e)

TNBC

Immune signature

BL2

Cell cycleDNA damage

BLcytokeratine

Growth signaling(EGF, IGF)

Low proliferation

ARPathway

IM

Claudin-Low

BL1

M

Normal BL

LA/LB

HER2e

LAR

PI3K mutations

EMT signature:cell motility

growth factor signaling (TFG6, Notch,

Wnt/β-catenin, Hedgehog)

Angiogenesis

MSL

Lehmann's classification

PAM50/claudin-low classificationReach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

http://www.clinicaloptions.com/oncology

TRIPLE NEGATIVE ABC

For non-BRCA-associated triple negative ABC, there are no data supporting different or specific CT recommendations.

Therefore, all CT recommendations for HER-2 negative disease also apply for triple negative ABC.


Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Lord and Ashworth Science (2017) Based on work of Yves Pommier and others

PARP INHIBITORS– mechanism of action (SYNTHETIC LETHALITY)

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Specific tumor cell killing

HR

rep

air

Few normal tissue effectsNormal tissue cells

DNA repair

DNA repair

Base excision DNA repair

Homologous recombination(HR) repair

BRCA1/BRCA2 deficientTumor cells

HR

rep

air

PARP inhibitor


PARP inhibitor


HR

rep

air

Tutt and Ashworth Cold Spring Harb Symp Quant Biol 2005;70:139–148; McCabe N et al. Cancer Res 2006;66:8109–8115

The principle of synthetic lethal tumour targeting

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

R

Potent PARP inhibitor

at MTD as continuous

exposure

Physician Choice

within SOC options

Capecitabine

or

Vinorelbine

or

Eribulin

or

Gemcitabine

gBRCA1 / BRCA2 Carriers

Advanced anthracycline

taxane resistant breast

cancer

Primary

endpoint

PFS

Niraparib – BRAVO Trial EORTC / BIG

Talazoparib– EMBRACA - NCT01945775

Olaparib - OLYMPIAD NCT02000622

National Institutes of Health, Available at: https://clinicaltrials.gov/ct2/results?term=NCT01945775 and https://clinicaltrials.gov/ct2/results?term=NCT02000622 . Accessed: September 27, 2015.

How does PARP inhibition compare with CT in ABC?

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

PARP Inhibitors in BRCA+ ABC

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

PARP Inhibitors in BRCA+ ABC

3 MONTHS DIFFERENCE IN PFS BUT BETTER QoLIMPACT ON OS?

COST: 7.000 €/month

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

PRECISION MEDICINE

• NOT RECOMMENDED for ROUTINE CLINICAL PRACTICE:

• Multigene panels

• Circulating tumour DNA (ctDNA) assessment

• Immunotherapy

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Checkpoint inhibitors: ABC and EBC are totally different immune settingsAtezolizumab approval was based in a 2.5 months PFS difference

9

Primary PFS analysis: ITT population

Schmid P, et al. IMpassion130.

ESMO 2018 (abstract 2056).NE, not estimable. Data cutoff: 17 April 2018. Median PFS durations (and 95% CI) are indicated on the plot. Median follow-up (ITT): 12.9 months.

0 3 6 9 12 15 18 21 24 27 30 33Months

No. at risk:Atezo + nab-P 451 360 226 164 77 34 20 11 6 1 NE NE

Plac + nab-P 451 327 183 130 57 29 13 5 1 NE NE NE

Atezo + nab-P

(N = 451)

Plac + nab-P

(N = 451)

PFS events, n 358 378

1-year PFS

(95% CI), %

24%

(20, 28)

18%

(14, 21)

7.2 mo(5.6, 7.5)

5.5 mo(5.3, 5.6)

100

80

60

40

20

0

Pro

gre

ss

ion

-fre

e s

urv

ival Stratified HR = 0.80

(95% CI: 0.69, 0.92)

P = 0.0025

10

Primary PFS analysis: PD-L1+ population


ESMO 2018 (abstract 2056).Data cutoff: 17 April 2018.

0 3 6 9 12 15 18 21 24 27 30 33Months

No. at risk:Atezo + nab-P 185 146 104 75 38 19 10 6 2 1 NE NE

Plac + nab-P 184 127 62 44 22 11 5 5 1 NE NE NE

7.5 mo(6.7, 9.2)

5.0 mo(3.8, 5.6)

100

80

60

40

20

0

Pro

gre

ssio

n-f

ree s

urv

ival Stratified HR = 0.62

(95% CI: 0.49, 0.78)

P < 0.0001

Atezo + nab-P

(n = 185)

Plac + nab-P

(n = 184)

PFS events, n 138 157

1-year PFS

(95% CI), %

29%

(22, 36)

16%

(11, 22)

11

Interim OS analysis: ITT populationa


ESMO 2018 (abstract 2056).

Data cutoff: 17 April 2018. Median OS durations (and 95% CI) are indicated on the plot. Median follow-up (ITT): 12.9 months.a For the interim OS analysis, 59% of death events had occurred. b Significance boundary was not crossed.

0 3 6 9 12 15 18 21 24 27 30 33 36Months

No. at risk:Atezo + nab-P 451 426 389 337 271 146 82 48 26 15 6 NE NE

Plac + nab-P 451 419 375 328 246 145 89 52 27 12 3 1 NE

21.3 mo(17.3, 23.4)

17.6 mo(15.9, 20.0)

100

80

60

40

20

0

Overa

ll s

urv

ival

Stratified HR = 0.84

(95% CI: 0.69, 1.02)

P = 0.0840b

Atezo + nab-P

(N = 451)

Plac + nab-P

(N = 451)

OS events, n 181 208

2-year OS

(95% CI), %

42%

(34, 50)

40%

(33, 46)

6

◆ Primary PFS analysis

(PFS tested in ITT and

PD-L1+ populations)

◆ First interim OS

analysis (OS tested

in ITT population, then,

if significant,

in PD-L1+ population)

IMpassion130 statistical testing


ESMO 2018 (abstract 2056).a α recycled if PFS/ORR testing is significant. Hazard ratio (HR)/P value–stopping boundaries are dependent on the OS analysis timing.

Atezo + nab-P

vs Plac + nab-P α = 0.05

PFS (primary)α = 0.01

OSa

• Interim

• Primary (α ≥ 0.04)

OS in ITT

population

OS in PD-L1+

population

1. PFS in ITT

populationα = 0.005

3. ORR in ITT


4. ORR in PD-L1+


2. PFS in PD-L1+

populationα = 0.005Rea

ch to

Rec

over

y Int

erna

tiona

l Con

fere

nce

2019

WHEN CHEMOTHERAPY IS NEEDED . . .

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

The cell cycle is the target of chemotherapy

Courtesy B. Sousa

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

CHEMOTHERAPY (general)

Both combination and sequential single agent CT are reasonable options. Based on the available data, we recommend sequential monotherapy as the preferred choice for MBC.

Combination CT should be reserved for patients with rapid clinical progression, life-threatening visceral metastases, or need for rapid symptom and/or disease control.


ALL guidelines are in agreement for this recommendationRea

ch to

Rec

over

y Int

erna

tiona

l Con

fere

nce

2019

• GOAL: to treat for as long as possible with a good QoL

• Then:

– TOXICITY PROFILE is crucial

– DOSE REDUCTIONS are acceptable and often needed (and better than interruptions)

– ORAL vs IV (convenient, cost-effective, maintain work responsibilities…)

– PATIENT PREFERENCES (oral treatment approaches and time saving drug delivery strategies are usually preferred by the patients)Rea

ch to

Rec

over

y Int

erna

tiona

l Con

fere

nce

2019

Which agents?

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Clinical Efficacy of Cytotoxic Agents

0

10

20

30

40

50

60

70

Vinorelbine Docetaxel Paclitaxel Doxorubicin Epirubicin Capecitabine Gemcitabine 5-FU

Ove

rall

Re

spo

nse

Rat

e (

%)

From: Hamilton A. J Clin Oncol. 2005; 23:1760-1775; Swart R. Medscape Reference. March 28, 2011, http://emedicine.medscape.com/article/1946040-overview.

Research question:

BEST SEQUENCE!?

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

http://emedicine.medscape.com/article/1946040-overview

LIPOSOMAL TECHNOLOGY“Old” agents with new technology

Doxorubicin Liposomal Doxorubicin Pegylated Liposomal Doxorubicin

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Reach

to R

ecov

ery I

nter

natio

nal C

onfe

renc

e 20

19

Reach to Recovery International Conference 2019

Documents

Transcript of Reach to Recovery International Conference 2019