Tras los inhibidores de ciclinas.¿Qué quimioterapia y cuándo?

Maria Vidal, MD, PhDMedical Oncology DepartmentTranslational Genomics and Targeted Therapeutics in Solid Tumorsmjvidal@clinic.cat

Viernes , 21 de junio de 2019

Consultancy/speakerPfizer, Lilly, Novartis, Roche, Daiichi

Disclosures

¿Qué quimioterapia y cuándo?

Enfermedad avanzada RE+ Her2 neg

No crisis visceralNo resistencia hormonal

Crisis visceralResistencia hormonal

Quimioterapia (mono/biterapia)Quimioterapia + bevacizumab?

1º línea: HT + Inhibidor Ciclina

Escasa/ No respuestaProgresión visceral

Respuesta mantenidaProgresión no visceral

Valorar ensayo clínicoHT + PI3K/ mTOR...HT...

Algoritmo actual de tratamiento

Datos biológicos de la progresión a inhibidores de ciclinas

50%30%

19%

<1%1%

PrimaryTumor

Tumor Evolution

Treatment

Cejalvo et al. Cancer Treatment Rev. 2018.

MetastasesBrain

Lung

Liver

Bone

Cejalvo et al. Cancer Res.2017

Finn R et al. SABCS 2017

Subtype in HR+/HER2-negative metastatic breast cancer

1. Prat et al. JAMA Oncology 2016

EGF3008 clinical trial (N=644)1 BOLERO-2 clinical trial (N=261)2

HER2-E

Non-HER2-E

0.8

0.6

Surv

ival

Pro

bab

ility

0.4

0.2

0.0

0 10 20 30Months

+ CensoredLogrank P=0.0015

40 50

1.0

Months

0.8

0.6

Ove

rall-

fre

e S

urv

ival

Pro

pro

tio

n

0.4

0.2

0.0

0 10 20 30

P-value <0.0001

40 50

1.0Luminal ALuminal BBasal-likeHER2-enriched

2. Prat et al. The Oncologist 2019

80% of the samples were from the primary tumor

HER2-enriched Subtype and Overall Survival inHR+/HER2-neg Metastatic Breast Cancer (N=905)

mPFS (months)

Palbociclib–letrozole: 24.8

Placebo–letrozole: 14.5

Finn R et al. NEJM 2016

N=455 (68.3%)

Finn R et al. SABCS 2017

50%

30%

19%

N=666

Intrinsic subtype in HR+/HER2-negative metastatic breast cancer (PALOMA-2 retrospective data)

Adapted from Ma et al. Nature Reviews 2015

Figure adapted from Asghar, et al. Nat Rev Drug Dis.

2015;14:130-146

Aleem & Arceci et al.

Front. Cell Dev. Biol 2015

The estrogen receptor (ER) signaling

pathway

The estrogen receptor (ER) signaling pathway

Adapted from Ma et al. Nature Reviews 2015

Estradiol

ERE

AP1 orSP1

CoA C

oA

CoRERE

Transcription

TranscriptionTranscription

Proliferation

PI3K

AKT

mTOR

RAS

RAF

MEK

MAPK

GRFs

GRB2

NOTCH

IGF1R; EGFR; HER2; MET;

FGFR

p38

JNK

CoA

Cytokines; hypoxia; stress

Cytosol

Nucleus

Nicholas C. Turner1, Ben O'Leary1, Ros Cutts2, Yuan Liu3, Sarah Hrebien2, Xin Huang3, Matthew Beaney2, Kerry Fenwick4, Fabrice Andre5, Sibylle Loibl6, Sherene Loi7, Isaac Garcia-

Murillas8, Cynthia Huang Bartlett9, Massimo Cristofanilli10

Cancer Discovery 2018

PIK3CA mutations

* both treatment groups combinedp values from McNemar’s test

Day

1

End

of

trea

tmen

t

Genetic landscape of resistance to CDK4/6 inhibition in ctDNA (ctDNA) analysis of the

PALOMA-3 trial

Few mutations acquired:

• RB1 mutations in palbo-arm (4.7%)

• PIK3CA mutations in both arms (8.3%)

• ESR1 mutations in both arms

¿Qué tratamientos reciben las pacientes tras progresión a inh cdk 4/6?

Characteristic

Palbociclib + Fulvestrant

(n=347)

Placebo + Fulvestrant

(n=174)Age, y

Median (min, max) 57 (30, 88) 56 (29, 80)<65, n (%) 261 (75.2) 131 (75.3)65, n (%) 86 (24.8) 43 (24.7)

Race, n (%)White 252 (72.6) 133 (76.4)Asian 74 (21.3) 31 (17.8)Black and other 20 (5.8) 9 (5.2)

Menopausal status at the study entry, n (%) Pre/perimenopausal 72 (20.7) 36 (20.7)Postmenopausal 275 (79.3) 138 (79.3)

Documented sensitivity to prior hormonal therapy, n (%)

Yes 274 (79.0) 136 (78.2)No 73 (21.0) 38 (21.8)

Visceral metastases, n (%) 206 (59.4) 105 (60.3)Prior lines of therapy in the metastatic setting, n (%)

0 74 (21.3) 40 (23.0)1 141 (40.6) 84 (48.3)2 94 (27.1) 37 (21.3)≥3 38 (11.0) 13 (7.5)

Cristofanilli, ESMO 2018

esmo.org

OVERALL SURVIVAL WITH PALBOCICLIB + FULVESTRANT IN WOMEN WITH HORMONE RECEPTOR–POSITIVE, HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2–NEGATIVE ADVANCED BREAST CANCER: ANALYSES FROM PALOMA-3

Massimo Cristofanilli,1 Dennis J. Slamon,2 Jungsil Ro,3 Igor Bondarenko,4 Seock-Ah Im,5 Norikazu Masuda,6 Marco

Colleoni,7 Angela DeMichele,8 Sherene Loi,9 Sunil Verma,10 Hiroji Iwata,11 Nadia Harbeck,12 Sibylle Loibl,13 Fabrice

André,14 Kathy Puyana Theall,15 Xin Huang,16 Carla Giorgetti,17 Cynthia Huang Bartlett,18 Nicholas C. Turner19

1Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Feinberg School of Medicine, Chicago, IL, USA; 2David Geffen School of

Medicine at University of California Los Angeles, Santa Monica, CA, USA; 3National Cancer Center, Goyang-si, South Korea; 4Dnipropetrovsk Medical

Academy, City Multiple-Discipline Clinical Hospital #4, Dnipropetrovsk, Ukraine; 5Seoul National University Hospital, Cancer Research Institute, Seoul

National University College of Medicine, Seoul, South Korea; 6NHO Osaka National Hospital, Osaka, Japan; 7Istituto Europeo di Oncologia, Milan, Italy; 8Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; 9Peter MacCallum Cancer Centre, University of Melbourne, Melbourne,

VIC, Australia; 10Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada; 11Aichi Cancer Center Hospital, Nagoya, Japan; 12Brustzentrum

der Universität Muenchen (LMU), Munich, Germany; 13German Breast Group, Neu-Isenburg, Germany; 14Institut Gustave Roussy, Villejuif, France; 15Pfizer Oncology, Cambridge, MA, USA; 16Pfizer Oncology, San Diego, CA, USA; 17Pfizer Oncology, Milan, Italy; 18Pfizer Oncology, Collegeville, PA,

USA; 19Royal Marsden Hospital and Institute of Cancer Research, London, UK

◆ HR+, HER2– ABC◆ Pre/peri- or

postmenopausal ◆ Progressed on prior

endocrine therapy

– On or within 12 months adjuvant

– On therapy for ABC

◆ ≤1 prior chemotherapy regimen for advanced cancer

Palbociclib + Fulvestrant (n=347)

Placebo + Fulvestrant (n=174)

Line of Subsequent Therapy

Treatment, n (%)* First Second Third or Greater First Second

Third or Greater

Any treatment received†

248 182 131 140 113 85

Chemotherapy 138 (56)

133 (73)

121 (92)

87 (62) 76 (67) 76 (89)

Antihormonal 100 (40)

40 (22) 38 (29) 52 (37) 29 (26) 31 (36)

mTOR kinase inhibitor

40 (16) 17 (9) 20 (15) 21 (15) 12 (11) 13 (15)

CDK4/6 inhibitors‡

6 (2) 2 (1) 6 (5) 9 (6) 6 (5) 15 (18)

SYSTEMIC SUBSEQUENT ANTICANCER THERAPIES BY CATEGORY (>10% IN ANY THERAPY LINE)

Cristofanilli, ESMO 2018

Palbociclib–Fulvestrant Group (N = 347) Placebo–Fulvestrant Group (N = 174)

Turner NC, N

Engl J Med 2018;

379:1926-1936

Systemic anticancer therapies received as first, second, and third or greater lines of subsequent treatment by more than 10% of the patients in either trial group who discontinued the intervention.

0 6 12 18 24 30 36 42 48 54

Time (Month)

0

10

20

30

40

50

60

70

80

90

100T

ime t

o C

hem

oth

erap

y P

ro

bab

ilit

y (

%)

Palbociclib+Fulvestrant (N=347) Median TCT=17.6 months 95% CI (15.2, 19.7)Placebo+Fulvestrant (N=174)

Median TCT=8.8 months 95% CI (7.3, 12.7)

HR=0.58395% CI (0.468, 0.727)1-sided p<0.000001

347 254 182 133 99 78 56 41 6PAL+FUL174 91 58 40 22 16 13 10 1PBO+FUL

Number of patients at risk

Time From Randomization to post-progression Chemotherapy (TCT)

Cristofanilli, ESMO 2018

TEST=time to end of subsequent treatment.

0 6 12 18 24 30 36 42 48 54Time (Month)

0

10

20

30

40

50

60

70

80

90

100

Tim

e t

o E

nd

of

Next

Th

era

py P

rob

ab

ilit

y (

%)

Palbociclib+Fulvestrant (N=347) Median TEST=18.8 months 95% CI (16.4, 20.5)Placebo+Fulvestrant (N=174) Median TEST=14.1 months 95% CI (12.0, 16.7)

HR=0.68495% CI (0.559, 0.836)1-sided p=0.0001

347 305 233 168 124 94 70 55 7PAL+FUL174 135 92 62 36 24 19 13 3PBO+FUL

Number of patients at risk

PFS1(inside trial) + PFS2 (first line post-progression)

Time From Randomization to END OF IMMEDIATE SUBSEQUENT LINE OF THERAPY POSTPROGRESSION (TEST)

Cristofanilli, ESMO 2018

0 5 10 15 20 25 30 35

Time (Month)

mPFS=11.2 mo

mPFS=4.6 mo

mOS=34.9 mo

mOS=28 mo

mTEST=18.8 mo

mTEST=14.1 mo

mTCT=17.6 mo

mTCT=8.8 mo

mTET=11.0 mo

mTET=4.6 mo

MAGNITUDE OF TREATMENT EFFECT WAS MAINTAINED ACROSS ENDPOINTS

6.6 months 6.9 months

PAL+FUL

PAL+FUL

PBO+FUL

PBO+FUL

mOS=median overall survival; mPFS=median progression-free survival.

OS

PFS

Cristofanilli, ESMO 2018

0 5 10 15 20 25 30 35

Time (Month)

mPFS=11.2 mo

mPFS=4.6 mo

mOS=34.9 mo

mOS=28 mo

mTEST=18.8 mo

mTEST=14.1 mo

mTCT=17.6 mo

mTCT=8.8 mo

mTET=11.0 mo

mTET=4.6 mo

MAGNITUDE OF TREATMENT EFFECT WAS MAINTAINED ACROSS ENDPOINTS

6.6 months 6.9 months

PAL+FUL

PAL+FUL

PAL+FUL

PAL+FUL

PBO+FUL

PBO+FUL

PBO+FUL

PBO+FUL

mTCT=median time from randomization to the start of postprogression chemotherapy; mTEST=median time from randomization to the end of the immediate subsequent line of postprogression therapy; mTET=median time from randomization to end of study treatment.

OS

TEST

TCT

PFS

TET

PAL+FUL

PBO+FUL

Cristofanilli, ESMO 2018

Phase III MONALEESA-7 Trial of Premenopausal Patients With

HR+/HER2− Advanced Breast Cancer Treated With Endocrine Therapy ±Ribociclib: Overall Survival Results

Hurvitz, etl al ASCO 2019Dr Sara Hurvitz

1906067504

Ribociclib + ET(n = 335)

Placebo + ET (n = 337)

Age (range), years 43 (25-58) 45 (29-58)

Race, n (%)WhiteAsianBlackOther/unknown

187 (56)99 (30)10 (3)

39 (12)

201 (60)99 (29)

9 (3)28 (8)

ECOG PS, n (%)a

012

245 (73)87 (26)

0

255 (76)78 (23)1 (< 1)

Previous neoadjuvant or adjuvant ET, n (%)NoYes

208 (62)127 (38)

196 (58)141 (42)

Previous chemotherapy for advanced disease, n (%)

47 (14) 47 (14)

Dr Sara Hurvitz

1906067504

Key Patient Baseline Characteristics

Hurvitz, etl al ASCO 2019

Dr Sara Hurvitz

Ribociclib + ET(n = 335)

Placebo + ET(n = 337)

Patients who discontinued study treatment, n

219 280

Any medication, n (%)a 151 (69) 205 (73)

Chemotherapy alone 49 (22) 80 (29)

Chemotherapy + hormone therapy/other

18 (8) 22 (8)

Hormone therapy alone

49 (22) 57 (20)

Hormone therapy + other

31 (14) 41 (15)

Other 4 (2) 5 (2)

• Receipt of any subsequent CDK4/6 inhibitors in patients who discontinued study treatment– Ribociclib arm: 22/219 patients

(10%) – Placebo arm: 52/280 (19%)

First Subsequent Therapy

1906067504

Subsequent Therapies After Treatment Discontinuation

Hurvitz, etl al ASCO 2019

Tripathy, NEJM 2019

Dr Sara Hurvitz

Ribociclib +

ETPlacebo + ET

Events/n 95/335 139/337

Median time to

CT, monthsNot reached 36.9

HR (95% CI) 0.596 (0.459-0.774)

Kaplan-

Meier

Estimate

Ribociclib

+ ET

Placebo +

ET

36 months 67.2% 53.8%

42 months 65.8% 49.0%

Landmark Analysis

1906067504

Time to First Subsequent Chemotherapy

Hurvitz, etl al ASCO 2019

Dr Sara Hurvitz

Ribociclib +

ETPlacebo + ET

Events/n 126/335 161/337

Median PFS2,

moNot reached 32.3

HR (95% CI) 0.692 (0.548-0.875)

Kaplan-

Meier

Estimate

Ribociclib

+ ET

Placebo +

ET

36 months 58.4% 46.2%

42 months 54.6% 37.8%

PFS 2: time from randomization to progression on the next line of therapy or death

Landmark Analysis

1906067504

Progression-Free Survival 2

Hurvitz, etl al ASCO 2019

Tolaney, ASCO 2018

Tolaney, ASCO 2018

Time to First Post-discontinuation Chemotherapy

Tolaney, ASCO 2018

Time to the Second Disease Progression or Death

Tolaney, ASCO 2018

Tolaney, ASCO 2018

Tolaney, ASCO 2018

Real world data

QT: 4,6m ET 3,7m

Ciruelos E, Garcia-Saenz JA. SEOM, 2017

Radiografía en España de 1L de QT tras la terapia endocrina

Población Global(167)

Base: Total pacientes en 1ª L de QT tras HT en cada grupo; Unidad: Porcentaje

0,60%

10,…

35,90%

53,40%

Eribulina

Antraciclinas

QT Oral

Taxanos

Eribulina Antraciclinas QT Oral Taxanos

% Pacientes en tratamiento

80%

8,3%

11,7 %

capecitabina capebeva vinorelbina

QT ORAL

(60)

45%

31,5%

21,3%

2,2%

nab-paclitaxel Paclibeva paclitaxel docetaxel

TAX ANO

S

(89)

1L de QT tras terapia endocrina en España

Trials ongoing

• Locally advanced or

Met TNBC and HR+

• Block / 20 slides of

tumor tissue @recurrence

• Rec◆rrences at ≥ 12

months after last dose

of chemotherapy for

early BC

• No prior

Chemotherapy for

LA/MBC

• Candidate for taxane

therapy

• Measurable disease

• PIK3CA/AKT/PTEN-

altered tumor

Targeted Patient

Population

•(Neo)Adjuvant

chemotherapy (Y/N)

•PIK3CA/AKT1/PTEN

alteration status

•Region (APAC/EU/NA/RoW)

•(Neo)Adjuvant

chemotherapy (Y/N)

•Prior PI3K/mTOR

inhibitor (Y/N)

•Region (APAC/EU/NA/RoW)

Paclitaxel 80 mg/m2 (IV

weekly D1, D8 and D15)

+

Placebo (PO daily, D1-21 of

28-day)

(n~67)

Paclitaxel 80 mg/m2

(IV weekly, D1, D8 and D15)

+

Ipatasertib 400mg (PO daily,

D1-21 of 28-day)

(n~134)

Stratification

Factors

A

B

N= 249 TNBC pts

N= 201 HR+ pts

2

1

Randomization

2:1Treatments *

Paclitaxel 80 mg/m2 (IV

weekly D1, D8 and D15)

+

Placebo (PO daily, D1-21 of

28-day)

(n~83)

Paclitaxel 80 mg/m2

(IV weekly, D1, D8 and D15)

+

Ipatasertib 400mg (PO daily,

D1-21 of 28-day)

(n~166)

2

1

Dis

ease

Pro

gre

ssio

n

Post Treatment

Follow Up

• Survival

• Patient Reported

Outcome

• New anti-cancer

therapy + outcomes

• Disease follow-up

(as needed for PFS)

* All patients should receive loperamide (2 mg BID or 4 mg QD) as prophylaxis for diarrhea in the first

cycle, and investigators are encouraged to continue this dosing for the remainder of the study using

their discretion based on clinical judgments – if allowed by local guidance.

IPATUNITY

Targeting non-Luminal disease by PAM50 with Pembrolizumab + Paclitaxel in Hormone Receptor (HR)-positive/HER2-negative advanced/metastatic breast

cancer

TATEN

Primary endpoint

Advanced/metastatic

HR+/HER2-negative

Breast Cancer

HER2-E or Basal-like

(PAM50)

Progression after

CDKinh

1st CT line in

metastatic setting

Pembrolizumab

200mg/kg 3w

+

Paclitaxel 80mg/m2

d1,8,15/21d

Metastatic biopsy: PAM50, DNAseqand ctDNA

Blood samples: Baseline, C2D1, PD

N= 46 (184)

KEY SECONDARY

OBJECTIVES: ORR

according to PD1 expresión, CBR, PFS, DoR, TTP, OS,

Safety,

OR

R

PI: Dr. Aleix PratCo-PI: Dr. Eva Ciruelos

SOLTI: innovative breast cancer research

Conclusiones

• Tras tratamiento con inhibidores de cdk 4/6 laspacientes recibirán QT cuando exista crisis visceral ourgencia de respuesta.

• El tratamiento con inhibidores cdk 4/6 retrasa eltiempo al inicio de la QT.

• Valorar tipo QT en función de QTs previas recibidas,comorbilidades y preferencias de la paciente(capecitabina, paclitaxel).

• Valorar inclusión de pacientes en estudios clínicos.