estrategias terapeúticas actuales y futuras en cáncer de mama … · fulvestrant 500 mg...

Estrategias terapeúticas actuales y

futuras en cáncer de mama avanzado

RE+ HER2- Dra E. Ciruelos

Servicio Oncología Médica

Hospital 12 de Octubre

Molecular Characteristics of Breast Cancer Subtypes

Subtype Luminal A Luminal B Basal-like HER2-enriched

TP53 pathway • TP53 mut (12%) • MDM2 gain (14%)

• TP53 mut (32%) • MDM2 gain (31%)

• TP53 mut (84%) • MDM2 gain (14%)

• TP53 mut (75%) • MDM2 gain (30%)

PIK3CA/PTEN pathway

• PIK3CA mut (49%) • PTEN mut/loss

(13%) • INPP4B loss (9%)


(24%) • INPP4B loss (16%)


(35%) • INPP4B loss (30%)


(19%) • INPP4B loss (30%)

RB1 pathway • Cyclin D1 amp (29%) • CDK4 gain (14%) • Low expression of

CDK2NC • High expression of

RB1

• Cyclin D1 amp (58%) • CDK4 gain (25%)

• RB1 mut/loss (20%) • Cyclin E1 amp (9%) • High expression of

CDKN2A • Low expression of

RB1


amp, amplification; CDK4, cyclin-dependent kinase 4; CDK2NC, cyclin-dependent kinase inhibitor; INPP4B, inositol phosphatase-4-phosphatase type II; MDM2, mouse double minute 2 homolog; mut, mutation; PIK3CA, phosphatidylinositol 3-kinase catalytic subunit alpha; PTEN, phosphatase and tensin homolog; RB1, retinoblastoma 1; TP53, tumor protein 53.

The Cancer Genomic Atlas Network. Nature 2012;490:61–70.

HR-positive/ HER2-negative

TNBC 13% HER2-positive/

HR-negative 8%

HR-positive/ HER2-positive

10%

Treatment Approvals for HR+ Metastatic Disease

1. Jordan VC. Steroids. 2007;72(13):829-842. 2. European Medicines Agency. Assessment Report pursuant to Article 30 of Directive 2001/83/EC, as amended. http://www.ema.europa.eu/docs/en _GB/document_library/Referrals_document/Arimidex_30/WC500109487.pdf. Accessed January 29, 2016. 3. European Medicines Agency. Assessment report pursuant to Article 30 of Directive 2001/83/EC,

as amended. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Femara_30/WC500128493.pdf. Accessed January 29, 2016. 4. European Medicines Agency. Press Release. European Medicines Agency recommends new contraindication for Fareston (toremifene). http://www.ema.europa.eu/docs/en_GB/document_library/Press

_release/2009/11/WC500014597.pdf. Accessed January 29, 2016. 5. US Food and Drug Administration. FDA-approved drug products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda /index.cfm?fuseaction= Search.DrugDetails. Accessed January 29, 2016. 6. Roche. Media Release. Avastin approved in Europe for first-line treatment of patients with advanced lung cancer.

http://www.roche.com/media/store/releases/med-cor-2007-08-24.htm. Accessed January 29, 2016. 7. European Medicines Agency. Assessment report for tyverb. http://www.ema.europa.eu /docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000795/WC500044960.pdf. Accessed January 29, 2016. 8. US Food and Drug Administration. Letter.

http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/125085s0241ltr.pdf. Accessed January 29, 2016. 9. US Food and Drug Administration. Letter. http://www.accessdata.fda.gov/ drugsatfda_docs/appletter/2012/022334Orig1s016ltrRepl.pdf. Accessed January 29, 2016. 10. Milani A, et al. World J Clin Oncol. 2014;5:990-1001. 11. Osborne CK, et al. Annu Rev Med. 2011;62:233-247.

12. Lange CA, et al. Endocr Relat Cancer. 2011;18:C19-C24. 13. Asghar U, et al. Nat Rev Drug Discov. 2015;14:130-146. 14. Baselga J. Oncologist. 2011;16(suppl 1):12-19. 15. Vicier C, et al. Breast Cancer Res. 2014;16:203. 16. US Food and Drug Administration. Letter. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/1998/20896ltr.pdf. Accessed January 29, 2016. 17. US Food and Drug Administration. Letter. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2010/201532s000ltr.pdf. Accessed January 29, 2016. 18. US Food and Drug Administration. Letter

http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2005/021660ltr.pdf. Accessed January 29, 2016.

*Various chemotherapy agents have been approved

(capecitabine, eribulin mesylate, paclitaxel),

but do not target HR+ disease specifically16–18

CDK, cyclin-dependent kinase; ER, estrogen receptor;

HR,hormone receptor; MBC, metastatic breast cancer;

mTOR, mammalian target of rapamycin;

PI3K, phosphoinositide 3-kinase

TIMELINE OF HR+ MBC TREATMENTS*

Understanding of estrogen, ER, and resistance11

Role of cyclin D1 and CDK4/612,13

Role of PI3K14 and mTOR15

1990 2000 2010

1995 Anastrozole EU

approval2

1996 Letrozole and Toremifene

EU approval3,4

1999 Exemestane US approval5

2002 Fulvestrant

US approval5 2015 Palbociclib

US approval5

2020

1973 Tamoxifen EU

approval1 Clinical development of new targeted therapies10

2012 Everolimus

US approval9

Primera línea

Aromatase inhibitors are the treatment of choice for first-line therapy of postmenopausal women with advanced HR-positive breast cancer2

On progression, second-line treatment options include other classes of aromatase inhibitors and ER antagonists (e.g. fulvestrant)2

• Resistance can develop to endocrine therapy,3 often leading to chemotherapy as the subsequent treatment option

• Current breast cancer research aims to overcome resistance to endocrine therapy, resulting in extended treatment with endocrine agents, and thus in a delay to chemotherapy initiation

“Current” Hormonal Treatments for 1st line HR-Positive Breast Cancer

Letrozole

Nonsteroidal

aromatase inhibitor

Anastrozole

Nonsteroidal

aromatase inhibitor

Fulvestrant

Estrogen receptor

downregulator

Exemestane

Steroidal

aromatase inhibitor

Frequently used endocrine treatment options for postmenopausal women with advanced HR-positive

breast cancer3

1. Cleator SJ, et al. Clin Breast Cancer 2009;Suppl 1:S6–S17 2. Baselga J, et al. N Engl J Med 2012;366:520–529; 3. Moy B, Goss PE. Clin Cancer Res 2006;12:4790–

4793; 4. NCCN Guidelines – Breast Cancer v2 2015.

FIRST: Updated TTP analysis 69% of patients had progressed*

Full analysis set, n=205

0 6 12 18 24 30 36 42 48

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n o

f p

ati

en

ts a

live

an

d p

rog

res

sio

n-f

ree

Time (months)

102 74 65 52 45 34 20 6 0

103 69 55 39 30 21 8 2 0

Fulvestrant 500 mg

Anastrozole 1 mg

HR=0.66

95% CI (0.47, 0.92) p=0.01

Fulvestrant 500 mg

Anastrozole 1 mg

Number of patients at risk:

0 12 18 42 48 Months 36 30 24 6

*After primary DCO, progression was determined by investigator opinion

Fulvestrant 500 mg

n=102

Anastrozole 1 mg

n=103

Number of progressions (%) 63 (61.8) 79 (76.7)

Median (months) 23.4 13.1

Robertson JFR et al. Br Can Res Treat 2012; 136:503–511

Rea

ctiv

e u

se o

nly

. Exc

lusi

ve M

edic

al &

Reg

ula

tory

Dep

artm

ent

Fulvestrant 500 mg

n=102

Anastrozole 1 mg

n=103

Dead, n (%) 63 (61.8) 74 (71.8)

Median OS (months) 54.1 48.4

102 90 84 77 57 47 31 24

103 90 80 72 49 39 21 14

0 6 12 18 24 30 36 42 108 0.0

0.2

0.4

0.6

0.8

1.0 P

rop

ort

ion

of

pa

tie

nts

ali

ve

Time (months)

Fulvestrant 500 mg

Anastrozole 1 mg

HR=0.70 95% CI (0.50, 0.98)

p=0.04

48 54 60 66 72 78 84 90 96 102

0 12 18 24 36 48 60 72 84 96 Months

Fulvestrant 500 mg

Anastrozole 1 mg

Number of patients at risk:

4

2

39

29

Patients not known to have died were right-censored at the last time they were known to be alive

Ellis MJ et al. J Clin Oncol 2015 Nov 10;33(32):3781-7

FIRST: OS at 75% maturity

Full analysis set, n=205

FALCON: PHASE III STUDY DESIGN

Randomised, double-blind, parallel-group, international, multicentre study

Follow-up for disease progression and survival

Randomisation of 450 patients was planned to achieve 306 progression events; if the true PFS HR was 0.69 this would provide 90% power for statistical significance at the 5% two-sided level (log-rank test)

Stratification factors: prior chemotherapy for advanced disease (yes / no); measurable vs. non-measurable disease (at baseline); locally advanced vs. metastatic disease

Subgroup analysis of PFS for pre-defined baseline covariates

• Postmenopausal women

• Locally advanced or metastatic breast cancer

• ER+ and / or PgR+ • HER2- • Endocrine therapy-

naïve

Fulvestrant 500 mg (500 mg IM on Days 0, 14 and 28, then every 28

days)

+ placebo to anastrozole

Anastrozole 1 mg (daily PO)

+ placebo to fulvestrant

Primary endpoint: PFSa

Secondary endpoints 1:1 • OSb

• ORR

• CBR

• DoR, EDoR

• DoCB, EDoCB

• HRQoL (FACT-B

total and TOI)

• Safety

Ellis M. ESMO 2016

A circle represents a censored observation

HR 0.797 (95% CI 0.637, 0.999); p=0.0486 Median PFS Fulvestrant: 16.6 months Anastrozole: 13.8 months

Number of patients at risk: Fulvestrant Anastrozole

230 232

187 194

171 162

150 139

124 120

110 102

96 84

81 60

63 45

44 31

24 22

11 10

2 0

0 0

Pro

po

rtio

n o

f p

atie

nts

aliv

e a

nd

p

rogr

essi

on

fre

e

Time (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.0 0 3 6 9 12 15 18 21 24 27 30 36 33 39

0.2

Fulvestrant (n=230) Anastrozole (n=232)

FALCON: PFS (ITT)

Post hoc interaction test p<0.01

A circle represents a censored observation

Without visceral disease With visceral disease

HR 0.59 (95% CI 0.42, 0.84) Median PFS Fulvestrant: 22.3 months Anastrozole: 13.8 months

Pro

po

rtio

n o

f p

atie

nts

aliv

e an

d p

rogr

essi

on

-fre

e

Time (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.0

0.2

Pro

po

rtio

n o

f p

atie

nts

aliv

e an

d p

rogr

essi

on

-fre

e

Time (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.0 0 5 10 15 20 25 30 35 40

0.2

0 5 10 15 20 25 30 35 40

HR 0.99 (95% CI 0.74, 1.33) Median PFS Fulvestrant: 13.8 months Anastrozole: 15.9 months



FALCON: PFS (visceral vs non-visceral)

FALCON: SECONDARY ENDPOINTS

aIn patients with measurable disease at baseline

Endpoint Fulvestrant

(N=230) Anastrozole (N=232)

ORRa 46.1% (89 / 193)

44.9% (88 / 196)

Odds ratio (95% CI)

1.07 (0.72, 1.61); p=0.729

CBR 78.3%

(180 / 230) 74.1%

(172 / 232)

Odds ratio (95% CI)

1.25 (0.82, 1.93); p=0.305

Median DoR 20.0 months 13.2 months - Median DoCB 22.1 months 19.1 months -

EDoR 11.4 months 7.5 months Ratio (95% CI)

1.52 (1.23, 1.89); p<0.001

EDoCB 21.9 months 17.5 months Ratio (95% CI)

1.26 (1.13, 1.39); p<0.001

Median time to deterioration in FACT-B total score

13.8 months 11.1 months HR (95% CI)

0.84 (0.66, 1.07); p=0.159




• TP53 mut (32%) • MDM2 gain (31%)

• TP53 mut (84%) • MDM2 gain (14%)

• TP53 mut (75%) • MDM2 gain (30%)

PIK3CA/PTEN pathway


(13%) • INPP4B loss (9%)


(24%) • INPP4B loss (16%)


(35%) • INPP4B loss (30%)


(19%) • INPP4B loss (30%)



RB1




RB1






HR-negative 8%


10%

Otto T. Nat Rev Cancer 2017

NN O

N

NH

O

N

N

NH

2

+

S

O

OO

OH

CDK 4/6 Inhibitors

• Orally active selective inhibitors of CDK4 and CDK6 kinases

• Inhibit cell proliferation and cellular DNA synthesis by preventing cell-cycle progression from G1 to S phase

• In vitro activity in retinoblastoma-positive tumor cell lines and primary tumors

• Low nanomolar concentrations block Rb phosphorylation, inducing G1 arrest in sensitive cell lines

• Specific cell cycle arrest in G1 phase

palbociclib

ribociclib

HN

N

N N

N

N

N

N H

O

abemaciclib

Palbociclib PD0332991 Pfizer

CDK4(9-11nM) and CDK6 (15nM)

G1 arrest

Phase III: breast, lung Phase II: breast, lung, HN, MM, AML, ALL, gastrointest, hepatocell, ovarian, prostate, melanoma, liposarc, urothelial, endometrial, astrocytoma, oligodendrog.

Ribociclib LEE011 Novartis

CDK4(10nM) and CDK6(39nM) G1 arrest

Phase III: breast Phase II: breast, melanoma, liposarc, prostate, lung, uterine, GI, ovarian, glioma, hepatocel, teratoma, pancreatic, colorectal

Abemaciclib LY835219 Eli Lilly

CDK4(2nM), CDK6(10nM), HIPK2(31nM), PIM1(50nM), CDK9(57nM), DYRK2(61nM), CK2(117nM), GSK3B(192nM)

G1 arrest Phase III: breast, lung Phase II: breast, lung, melanoma, mantle cell lymphoma

CDK 4/6 Inhibitors

PALOMA-1/TRIO-18 Study Design (NCT00721409)

• Randomized phase 2 open-label trial involving 50 centers in 12 countries

• Key eligibility criteria: inoperable ER-positive/HER2-negative locally recurrent disease, postmenopausal status, no prior therapy for advanced breast cancer, no prior CDK inhibitors, no letrozole within 12 months, no prior/current brain metastases, RECIST 1.0, ECOG ≤1, adequate bone marrow and renal function

• Expected an improvement in mPFS from 9 to 13,5 m (80% power, one-sided alpha 0.10, HR 0,64)

Palbociclib 125 mg/d† + Letrozole 2.5

mg/d

Letrozole 2.5 mg/d

ER+/HER2− advanced

breast cancer

*Randomization stratified by disease site and disease-free interval. † Palbociclib schedule 3/1 (28-day cycles).

1:1

R

A

N

D

O

M

I

Z

A

T

I

O

N

*

Palbociclib 125 mg/d† + Letrozole 2.5

mg/d

Letrozole 2.5 mg/d

ER+/HER2− advanced

breast cancer with CCND1

amplification and/or loss of

p16

1:1

n=66 n=99

R

A

N

D

O

M

I

Z

A

T

I

O

N

*

Cohort 1 Cohort 2

Finn RS et al. Lancet Oncol 2015; 16:25-35.

PFIZER CONFIDENTIAL

PALOMA-1/TRIO-18: PFS (ITT Population)

0

10

20

30

40

50

60

70

80

90

100

Number at risk Palbociclib plus letrozole

Letrozole 5 1

8 3

28 14

21 6

47 28

36 19

84 81

13 3

67 48

60 36

1

Palbociclib plus letrozole Letrozole

HR 0.488 (95% CI 0.319–0.748; one-sided P=0.0004)

Pro

gres

sio

n-f

ree

surv

ival

, %

0 4 8 12 16 20 24 28 32 36 40

Time, months

mPFS 20,2 vs 10,2 m

.. Finn RS et al. Lancet Oncol 2015; 16:25-35.

mFU 28 m

PALOMA-2: Phase III Study Design in Postmenopausal Patients with ER+, HER2– Advanced Breast Cancer

• Phase III, randomized, double-blind trial at 186 centers in 17 countries

• Treatment continued until objective disease progression, unacceptable toxicity, or withdrawal of consent. Crossover was not allowed

• Palbociclib/placebo dose reductions were allowed per protocol. Letrozole dose reductions were not permitted

aRandomization stratified by disease site (visceral/non-visceral), disease-free interval, and prior (neo)adjuvant hormonal therapy

b3 weeks on/1 week off of a 4-week cycle

ECOG PS, Eastern Cooperative Oncology Group Performance Status; ER+, estrogen receptor-positive; HER2–, human epidermal growth factor receptor 2-negative; NSAI, non-steroidal aromatase inhibitor; QD, once a day; RECIST,

Response Evaluation Criteria In Solid Tumors

clinicaltrials.gov NCT01740427;

Finn RS, et al. N Engl J Med 2016 Nov 17;375(20): 1925–1936

Placebo (3/1 schedule)

+ letrozole (2.5 mg QD)

Palbociclib (125 mg QD, 3/1 scheduleb)

+ letrozole (2.5 mg QD)

• Postmenopausal

• ER+, HER2– advanced breast cancer

• No prior systemic treatment for advanced disease

• Prior (neo)adjuvant treatment with anastrozole or letrozole was allowed if the disease-free interval was ≥12 months from completion of therapy

• Measurable disease according to RECIST v1.1 or bone-only disease

• ECOG PS 0–2

• Adequate organ function

• No advanced, symptomatic visceral spread at risk of short-term life-threatening complications

RA

ND

OM

IZA

TIO

N

N=666a

2:1

PALOMA-2: Investigator-assessed PFS (ITT Population)

• As initial therapy for postmenopausal ER+/HER2– advanced breast cancer, palbociclib + letrozole significantly improved PFS compared with placebo + letrozole

CI, confidence interval; ER+, estrogen receptor-positive; HER2–, human epidermal growth factor receptor 2-negative; HR, hazard ratio; ITT, intention to treat;

LET, letrozole; NE, not estimable; PAL, palbociclib; PCB, placebo; PFS, progression-free survival Finn RS, et al. N Engl J Med 2016 Nov 17;375(20): 1925–1936

Time from randomization (months)

444 395 360 328 295 263 238 154 69 29 10 2 222 171 148 131 116 98 81 54 22 12 4 2

PAL + LET PCB + LET

Number of patients at risk

Palbociclib + letrozole (n=444)

Placebo + letrozole (n=222) Median (95% CI) PFS

14.5 months (12.9–17.1)

Median (95% CI) PFS

24.8 months (22.1–NE)

PF

S p

rob

abili

ty (

%)

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

0

10

20

30

40

50

60

70

80

90

100

PAL+LET (N=444)

PCB+LET (N=222)

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

Median (95% CI) PFS, mo 24.8 (22.1–NE) 14.5 (12.9–17.1)

HR (95% CI) 1-sided P value

0.58 (0.46–0.72) <0.000001

PALOMA-2: PFS Subgroup Analysis (ITT, Investigator Assessment)

• The PFS advantage for palbociclib + letrozole over letrozole alone was consistent across subgroups

Finn RS, et al. N Engl J Med 2016 Nov 17;375(20): 1925–1936

Subgroup Palbociclib–Letrozole,

n (%) Placebo–Letrozole,

n (%) HR (95% CI)

All randomized patients 444 (100) 222 (100) 0.58 (0.46–0.72)

Age <65 years ≥65 years

263 (59.2) 181 (40.8)

141 (63.5) 81 (36.5)

0.57 (0.43–0.74) 0.57 (0.39–0.84)

Race White Asian

344 (77.5) 65 (14.6)

172 (77.5) 30 (13.5)

0.58 (0.45–0.74) 0.48 (0.27–0.87)

Site of metastatic disease at baseline

Viscerala

Non-visceral 214 (48.2) 230 (51.8)

110 (49.5) 112 (50.5)

0.63 (0.47–0.85) 0.50 (0.36–0.70)

Prior hormonal therapy Yes No

249 (56.1) 195 (43.9)

126 (56.8) 96 (43.2)

0.53 (0.40–0.70) 0.63 (0.44–0.90)

Disease-free interval Newly metastatic disease

≤12 months >12 months

167 (37.6) 99 (22.3)

178 (40.1)

81 (36.5) 48 (21.6) 93 (41.9)

0.67 (0.46–0.99)

0.50 (0.33–0.76) 0.52 (0.37–0.73)

Region North America

Europe Asia/Pacific

168 (37.8) 212 (47.7) 64 (14.4)

99 (44.6) 95 (42.8) 28 (12.6)

0.61 (0.43–0.85)

0.57 (0.41–0.80) 0.49 (0.27–0.87)

ECOG performance status 0 1/2

257 (57.9) 187 (42.1)

102 (45.9) 120 (54.1)

0.65 (0.47–0.90) 0.53 (0.39–0.72)

Bone-only disease at baseline Yes No

103 (23.2) 341 (76.8)

48 (21.6) 174 (78.4)

0.36 (0.22–0.59) 0.65 (0.51–0.84)

Measurable disease Yes No

338 (76.1) 106 (23.9)

171 (77.0) 51 (23.0)

0.66 (0.52–0.85) 0.35 (0.22–0.57)

Prior chemotherapy Yes No

213 (48.0) 231 (52.0)

109 (49.1)

113 (50.9)

0.53 (0.40–0.72) 0.61 (0.44–0.84)

Most recent therapy Aromatase inhibitor Antiestrogen

91 (20.5) 154 (34.7)

44 (19.8)

75 (33.8)

0.55 (0.34–0.88) 0.56 (0.39–0.80)

Number of disease sites 1 ≥2

138 (31.1) 306 (68.9)

66 (29.7)

156 (70.3)

0.51 (0.34–0.77) 0.61 (0.47–0.79)

Histopathological classification Ductal carcinoma Lobular carcinoma

356 (80.2) 68 (15.3)

184 (82.9) 30 (13.5)

0.59 (0.46–0.75) 0.46 (0.27–0.78)

In favor of PAL + LET In favor of PCB + LET

0.15 0.2 0.4 0.6 0.8 1.00 2.00

Subgroup Analysis of PFS by Biomarker

HR=hazard ratio; LET=letrozole; PAL=palbociclib; PCB=placebo; PFS=progression-free survival.

n HR (95% CI)

All patients 666 0.58 (0.46–0.72)

ER+ ER–

504 62

0.57 (0.44–0.74) 0.41 (0.22–0.75)

Rb+ Rb–

512 51

0.53 (0.42–0.68) 0.68 (0.31–1.48)

Cyclin D1+ Cyclin D1–

549 15

0.56 (0.44–0.71) 1.0 (0.29–3.46)

p16+ p16–

466 84

0.52 (0.40–0.67) 0.73 (0.39–1.36)

Ki-67 ≤20% Ki-67 >20%

318 235

0.53 (0.38–0.74) 0.57 (0.41–0.79)

0 1 2 3 4

HR (95% CI)

Favors PAL+LET Favors PCB+LET

Percentile n HR (95% CI)

All patients 666 0.58 (0.46–

0.72)

ER status

≤25th >25th to

<75th ≥75th

142 282 142

0.50 (0.32–0.78) 0.53 (0.37–0.74) 0.65 (0.41–1.05)

Rb status

≤25th >25th to

<75th ≥75th

154 249 160

0.57 (0.36–0.88) 0.46 (0.32–0.67) 0.63 (0.42–0.95)

Cyclin D1 status

≤25th >25th to

<75th ≥75th

141 247 176

0.41 (0.26–0.65) 0.69 (0.48–1.00) 0.52 (0.34–0.78)

p16 status

≤25th >25th to

<75th ≥75th

140 258 152

0.74 (0.46–1.20) 0.62 (0.44–0.89) 0.33 (0.21–0.52)

0 .0 0 .5 1 .0 1 .5HR (95% CI)

Favors PAL+LET Favors PCB+LET

Qualitative Analysis Quantitative Analysis

MONALEESA-2: A Phase III, Double-blind, Placebo-controlled Study of Ribociclib + Letrozole

– Tumor assessments were performed every 8 weeks for 18 months, then every 12 weeks thereafter

– Final analysis planned after 302 PFS events

• 93.5% power to detect a 33% risk reduction (hazard ratio 0.67) with one-sided α=2.5%

– Interim analysis planned after ~70% PFS events

• Two-look Haybittle–Peto stopping criteria: hazard ratio ≤0.56 and p<0.0000129

• PFS, progression-free survival. • MONALEESA-2 is registered at ClinicalTrials.gov (NCT01958021).

Randomization (1:1)

Stratified by the presence/absence

of liver and/or lung metastases

Ribociclib (600 mg/day) 3-weeks-on/1-week-off

+ Letrozole (2.5 mg/day)

n=334

Placebo +

Letrozole (2.5 mg/day) n=334

Primary endpoint • PFS (locally assessed per

RECIST v1.1)

Secondary endpoints • Overall survival (key) • Overall response rate • Clinical benefit rate • Safety

• Postmenopausal women with HR+/HER2– advanced breast cancer

• No prior therapy for advanced disease

• N=668

PFS (Investigator Assessment)

Ribociclib + Let n=334

Placebo + Let n=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

– 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

P

rogr

essi

on

-fre

e 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: PFS

Hortobagyi G, ESMO 2016

Median FU 15,3m

*Excludes patients who had received tamoxifen. ER, estrogen receptor; EXE, exemestane; NSAI, non-steroidal aromatase inhibitor; PgR, progesterone receptor; PgR+, PgR-positive; PS, performance status. 1. Hortobagyi GN et al. Ann Oncol 2016;27(Suppl 6): abstr LBA 3552 (oral).

MONALEESA-2: Efficacy Subgroup analysis1

Subgroup n (%) Hazard ratio (95% CI)

All patients 668 (100) 0.556 (0.429–0.720)

Age <65 years ≥65 years

373 (56) 295 (44)

0.523 0.608

(0.378–0.723) (0.394–0.937)

Race Asian

Non-Asian 51 (7.6) 568 (85)

0.387 0.607

(0.166–0.906) (0.459–0.804)

ECOG PS 0 1

407 (61) 261 (39)

0.588 0.528

(0.422–0.820) (0.348–0.801)

ER/PgR status ER+ and PgR+

Other 546 (82) 122 (18)

0.616 0.358

(0.461–0.823) (0.198–0.647)

Liver or lung involvement No Yes

295 (44) 373 (56)

0.547 0.569

(0.360–0.832) (0.409–0.792)

Bone-only disease No Yes

521 (78) 147 (22)

0.541 0.690

(0.405–0.723) (0.381–1.249)

De novo disease No Yes

441 (66) 227 (34)

0.603 0.448

(0.447–0.814) (0.267–0.750)

Prior (neo)adjuvant ET

NSAI and others*

Tamoxifen or EXE None

53 (7.9) 293 (44) 322 (48)

0.448 0.570 0.570

(0.193–1.038) (0.393–0.826) (0.380–0.854)

Prior (neo)adjuvant chemotherapy No Yes

377 (56) 291 (44)

0.548 0.548

(0.373–0.806) (0.384–0.780)

Favors Placebo + Letrozole

Favors Ribociclib + Letrozole

0.556

0,1 1 100.556

NP4 1702046634

MONALEESA 2: Secondary Endpoints

Ribociclib + Letrozole

Placebo + Letrozole

Overall survival data were immature at the cut-off date for interim analysis

41

28

0

20

40

60

80

100

ORR

All Patients

p=0.000155

Rat

e (

%)

Overall Response Rate

53

37

0

20

40

60

80

100

ORR

Patients With Measurable Disease

p=0.00028

Rat

e (

%)

Overall Response Rate

Clinical benefit rate in patients with measurable disease: 80% ribociclib arm vs. 72% placebo arm (p=0.02)

Tratamiento hormonal de primera línea: Mediana PFS (m)

letrozol Anastr. FIRST FALCON PALOMA 2 MONALEESA 2

Anastr. Fulvest. Anastr. Fulvest. Letrozol Letrozol + Palbo.

Letrozol Letrozol + Ribo.

9,4 10,7 13,1 23,4 13,1 16,6 14,5 24,8 16 25,3

Segunda y sucesivas líneas

‘Faslodex®: Prospective Combined Analysis (Trials 0020 and 0021) — Time to Progression

Robertson JFR, Osborne CK, Howell A, et al. Cancer 2003; 98:229-238

Hazard ratio (95.14% CI): 0.95; (0.82–1.10); p=0.48

Median TTP: Fulvestrant 5.5 months Anastrozole 4.1 months

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

0 6 12 18 24 30 36

Median follow-up 15.1 months

Time to progression (months)

Pro

po

rtio

n n

ot

pro

gre

sse

d

Fulvestrant 250mg

Anastrozole 1mg

1.0

Median PFS 5,5 vs 6,5 m

Hazard Ratio (95% CI) = 0.80 (0.68 - 0.94) p-value = 0.006

Fulvestrant 500 mg Fulvestrant 250 mg

0 4 8 12 16 20 24 28 32 36 40 44 48

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n o

f p

atie

nts

pro

gres

sio

n f

ree

Time (Months)

374 199 144 85 60 35 25 12 4 3 1 1 Fulvestrant 250mg

362 216 163 113 90 54 37 19 12 7 3 2 Fulvestrant 500mg

Number at risk

0

0

Faslodex® 500 mg reduce the risk of progression by 20% compared with the dose of 250 mg

CONFIRM: PFS curves by treatment arm

Di Leo A, Jerusalem G, Petruzelka L, et al. J Clin Oncol 2010; 28:4594-4600




• TP53 mut (32%) • MDM2 gain (31%)

• TP53 mut (84%) • MDM2 gain (14%)

• TP53 mut (75%) • MDM2 gain (30%)

PIK3CA/PTEN pathway


(13%) • INPP4B loss (9%)


(24%) • INPP4B loss (16%)


(35%) • INPP4B loss (30%)


(19%) • INPP4B loss (30%)



RB1




RB1






HR-negative 8%


10%

LA COMBINACIÓN DE EVEROLIMUS Y TRATAMIENTO HORMONAL

Primer ejemplo de la optimización del tratamiento hormonal en

pacientes pretratadas

EVE, everolimus; EXE, exemestane; PFS, progression-free survival; TAM, tamoxifen.

1. From Baselga J, et al. N Engl J Med 2012;366:520–529 © 2012 Massachusetts Medical Society.

2. Bachelot T, et al. J Clin Oncol 2012; 30:2718–2724 © 2012 American Society of Clinical Oncology.

Figures reproduced with permission of Massachusetts Medical Society and American Society of Clinical Oncology.

TAMRAD2

Overall survival (Sept 2011) in a Ph II study of postmenopausal women

with HR+/HER2– advanced BC treated with tamoxifen ± everolimus

BOLERO-21

PFS (local assessment) in a Ph III study of postmenopausal women

with HR+/HER2– advanced BC treated exemestane ±everolimus

0

80

60

40

20

100

0 8 16 24 32 40 P

rob

ab

ilit

y o

f S

urv

iva

l (%

) Months

No. at risk

TAM 57 56 54 53 52 54 44 43 39 37 37 36 32 26 20 16 8 6 5 2 1

TAM + EVE 54 54 53 52 50 50 50 50 47 47 47 44 38 33 28 22 15 10 8 3 0

HR = 0.45 (95% Cl, 0.24-0.81)

N (%) of events (TAM vs TAM + EVE: 31 (54%) vs 16 (30%)

P = 0.007 (exploratory analysis) 0

80

60

40

20

100

0 12 24 36 48 60 72

Pro

ba

bilit

y o

f E

ve

nt

(%)

Weeks No. at risk

Everolimus 485 398 294 212 144 108 75 51 34 18 8 3 3 0

Placebo 239 177 109 70 36 26 16 14 9 4 3 1 0 0

HR = 0.43 (95% Cl, 0.35–0.54)

P<0.001 by log-rank test

EVE + EXE

(median PFS, 7,8 mo)

Placebo + EXE

(median PFS, 3,2 mo)

TAM TAM + EVE

FULVESTRANT +/- EVEROLIMUS Phase II rando.

IA pretreated < 1 line chemo

Kornblum, SABCS 2016

Acontecimientos Adversos relacionados con Everolimus

Acontecimiento Adverso**

Cualquier Grado BALLET ESPAÑA

n (%)

Grado 3/4 n (%) BALLET

ESPAÑA

BOLERO2 Grado 3/4 n (%)

Estomatitis 272 (63) 40 (10) 38 (8)

Astenia 108 (25) 20 (5) 24 (5)

Erupción 76 (18) 5 (1) 5 (1)

Neumonitis 60 (14) 13 (3) 14 (3)

Diarrea 56 (13) 4 (1) 14 (3)

Falta de apetito

56 (13) 4 (1) 5 (1)

Los AAs que ocasionaron la retirada definitiva del paciente con mayor frecuencia

durante todo el período de observación del estudio fueron neumonitis, astenia y

estomatitis

Acontecimiento Adverso*

Cualquier Grado n (%)

Grado 3/4 n (%)

Cualquier AA 372 (87) 139 (32)

Isoform-Specific PI3K Inhibition PI3K Inhibitors in Late-Stage Clinical Development

Regulatory

subunit

Catalytic subunit

(4 isoforms: α, β, γ, δ)

PI3K1

p85

p110

1. Courtney KD, et al. J Oncol. 2010;28:1075-1083; 2. Maira SM, et al. Mol Cancer Ther. 2012;11:317-328;

2. 3. Dienstmann R, et al. Mol Cancer Ther. 2014;13:1021-1031;

3. 4. Fritsch C, et al. Mol Cancer Ther. 2014;13:1117-1129; 5. Ndubaku CO, et al. J Med Chem. 2013;56:4597-4610

Alpelisib3,4

PI3Kα inhibitor

Taselisib3,5

PI3Kα,γ,δ inhibitor

α

α

γ δ β

γ δ

Buparlisib2,3 Pan-PI3K inhibitor

α

BELLE 2: Buparlisib Plus Fulvestrant in AI pretreated ABC PFS in ctDNA PIK3CA Mutations

ctDNA PIK3CA Mutant n=200

Buparlisib + Fulvestrant

n=87

Placebo + Fulvestrant

n=113


7.0 (5.0–10.0)

3.2 (2.0–5.1)

HR (95% CI) 0.56 (0.39–0.80)

One-sided nominal P value <0.001

ctDNA PIK3CA Non-mutant n=387

Buparlisib + Fulvestrant

n=199


n=188


6.8 (4.7–8.5)

6.8 (4.7–8.6)

HR (95% CI) 1.05 (0.82–1.34)

One-sided nominal P value 0.642

Pro

ba

bilit

y o

f

Pro

gre

ss

ion

-fre

e S

urv

iva

l, %

Time (Months)

100

60

0

80

40

20

0 4 8 14 18 2 6 10 12 16 20 26 28 22 24

Buparlisib + fulvestrant

(n/N=124/199)

Placebo + fulvestrant (n/N=126/188)

Pro

ba

bilit

y o

f

Pro

gre

ss

ion

-fre

e S

urv

iva

l, %

Time (Months)

100

60

0

80

40

20

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

Buparlisib + fulvestrant (n/N=48/87)

Placebo + fulvestrant (n/N=90/113)

CI, confidence interval; ctDNA, circulating tumor DNA; HR, hazard ratio; PFS, progression-free survival.

• PFS results by independent central review were consistent with local assessment:

– HR 0.57 (95% CI: 0.44–0.74; one-sided p<0.001)

BELLE 3: Progression-free Survival per Investigator Assessment (Primary Endpoint)

Everolimus pretreated ABC

CI, confidence interval; HR, hazard ratio.

6-month PFS rate:

31% vs. 20%

100

80

60

40

20

0

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

Time, Months

Pro

bab

ility

of

P

rogr

essi

on

-fre

e Su

rviv

al, %

Full Population (N=432)

Buparlisib +

Fulvestrant

n=289

Placebo +

Fulvestrant

n=143

Median PFS,

months (95% CI)

3.9

(2.8–4.2)

1.8

(1.5–2.8)

HR (95% CI) 0.67 (0.53–0.84)

One-sided p-value <0.001

Di Leo, SABCS 2016

BELLE 3: Progression-free Survival by PIK3CA Status

100

80

60

40

20

0

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

100

80

60

40

20

0

20 18 16 14 12 10 8 6 4 2 0

Pro

bab

ility

of

PFS

, %

Tissue

(mutant)

Buparlisib

+

Fulvestrant

Placebo +

Fulvestra

nt

Median PFS,

months (95%

CI)

4.7

(2.9–6.7)

1.4

(1.4–2.2)

HR (95% CI) 0.39 (0.23–0.65);

p<0.001

PCR, polymerase chain reaction; WT, wild-type. p-values are one-sided.

100

80

60

40

20

0

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

Pro

bab

ility

of

PFS

, %

100

80

60

40

20

0

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

Primary tumor tissue (PCR) N=321

PIK3CA mutant:

34%

Time, Months Time, Months

Tissue (WT)

Buparlisib

+

Fulvestrant

Placebo +

Fulvestra

nt

Median PFS,

months (95%

CI)

2.8

(2.0–3.7)

2.7

(1.4–2.9)

HR (95% CI) 0.83 (0.60–1.14);

p=0.117

ctDNA (WT)

Buparlisib

+

Fulvestrant

Placebo +

Fulvestra

nt

Median PFS,

months (95%

CI)

3.9

(2.8–4.3)

2.7

(1.5–3.6)

HR (95% CI) 0.73 (0.53–1.00);

p=0.026

ctDNA

(mutant)

Buparlisib

+

Fulvestrant

Placebo +

Fulvestra

nt

Median PFS,

months (95%

CI)

4.2

(2.8–6.7)

1.6

(1.4–2.8)

HR (95% CI) 0.46 (0.29–0.73);

p<0.001

ctDNA samples at study entry

(BEAMing) N=348

PIK3CA mutant: 39%

Mutant Wild-type

Di Leo, SABCS 2016




• TP53 mut (32%) • MDM2 gain (31%)

• TP53 mut (84%) • MDM2 gain (14%)

• TP53 mut (75%) • MDM2 gain (30%)

PIK3CA/PTEN pathway


(13%) • INPP4B loss (9%)


(24%) • INPP4B loss (16%)


(35%) • INPP4B loss (30%)


(19%) • INPP4B loss (30%)



RB1




RB1






HR-negative 8%


10%

Turner NC et al. N Engl J Med 2015; 373:209-219

PALOMA3 Study Design

Placebo (3 wks on/ 1wk off)

+ Fulvestrant†

(500 mg IM q4w)

Palbociclib (125 mg QD;

3 wks on/1 wk off) +

Fulvestrant† (500 mg IM q4w)

†administered on Days 1 and 15 of Cycle 1.

● Visceral metastases

● Sensitivity to prior hormonal therapy

● Pre-/peri- vs Post-menopausal

Clinicaltrials.gov NCT01942135

2:1 Randomization

N=521

Stratification:

• Post-menopausal patients must have progressed on prior aromatase inhibitor therapy.

n=347

n=174

• HR+, HER2– ABC

• Pre-/peri-* or post-menopausal

• Progressed on prior endocrine therapy:

– On or within 12 mo adjuvant

– On therapy for ABC

• ≤1 prior chemotherapy regimen for advanced cancer

*All received goserelin.

Obj 1º: PFS mPFS 6 a 9,3 meses; HR 0,64, power 90%; 1 alfa 2,5%

PALOMA-3 Final Analysis: Investigator-Assessed PFS (ITT Population)

Cristofanilli M, et al. Lancet Oncol 2016 [Published online 2 March 2016; http://dx.doi.org/10.1016/S1470-2045(15)00613-0]

PAL + FUL (n=347)

PLACEBO + FUL (n=174)

Median PFS, mos (95% CI) 9.5 (9.2─11.0) 4.6 (3.5─5.6)

HR (95% CI) 0.46 (0.36─0.59)

P value <0.0001

PFS

(%

)

Time (months)

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 15 11 12 13 14

Placebo + fulvestrant

Palbociclib + fulvestrant

347 333 281 273 247 244 202 197 91 85 32 0 23 7 7 1 Palbociclib + fulvestrant

174 165 112 105 83 80 59 58 22 22 13 0 7 2 1 0 Placebo + fulvestrant

Number at risk

PALOMA-3 Final Analysis: PFS by Patient Subgroup (1)

PFS, progression-free survival; CI, confidence interval. Full data presented in:



median PFS (95%CI)


median PFS (95%CI) Hazard ratio

(95% CI) Pinteraction

Menopausal status at study entry

0.89

Premenopausal or perimenopausal

9.5 (7.4–NE) 5.6 (1.8–7.6) 0.50 (0.29–0.87)

Postmenopausal 9.9 (8.5–11.0) 3.9 (3.5–5.5) 0.45 (0.34–0.59) Site of metastatic disease 0.82 Visceral 8.0 (7.5–9.5) 3.5 (2.0–5.3) 0.47 (0.34–0.63) Non-visceral 11.2 (9.9–NE) 5.6 (4.6–10.9) 0.43 (0.28–0.67) Number of disease sites 0.43 1 11.2 (9.9–NE) 9.3 (5.5–NE) 0.55 (0.34–0.90) 2 11.0 (7.5–NE) 3.6 (1.9–5.6) 0.37 (0.24–0.59) ≥3 7.6 (7.4–9.5) 3.4 (1.9–3.7) 0.40 (0.28–0.59) Disease-free interval 0.16 ≤24 months 7.2 (2.5–9.2) 5.4 (1.8–9.3) 0.83 (0.43–1.59) >24 months 9.9 (9.3–11.2) 5.5 (3.5–7.3) 0.48 (0.35–0.68) Previous lines of endocrine therapy

0.75

1 9.5 (7.6–NE) 4.6 (3.4–5.6) 0.42 (0.29–0.60) 2 9.9 (7.5–13.9) 5.1 (2.8–7.2) 0.46 (0.31–0.69) ≥3 9.4 (7.5–NE) 3.9 (1.8–NE) 0.61 (0.30–1.24) Previous endocrine therapy 0.63 Aromatase inhibitor only 9.5 (7.6–13.9) 3.7 (2.1–5.5) 0.39 (0.27–0.57) Tamoxifen only 9.5 (7.5–NE) NE (1.7–NE) 0.61 (0.28–1.33) Aromatase inhibitor and tamoxifen

9.5 (7.6–11.2) 4.2 (3.5–7.2) 0.50 (0.35–0.71)

Favours palbociclib

plus fulvestrant

Favours placebo

plus fulvestrant

0.125 0.25 0.5 1 2 4 8

PALOMA-3 Final Analysis: PFS by Patient Subgroup (2)

PFS, progression-free survival; CI, confidence interval. Full data presented in:



median PFS (95%CI)


median PFS (95%CI) Hazard ratio

(95% CI) Pinteraction

Sensitivity to previous hormonal therapy

0.13

Yes 10.2 (9.4–11.2) 4.2 (3.5–5.6) 0.42 (0.32–0.56) No 7.4 (5.6–9.2) 5.4 (1.9–7.4) 0.64 (0.39–1.07) The purpose of most recent therapy

0.39

Neoadjuvant or adjuvant treatment

9.5 (7.4–NE) 5.4 (2.1–10.9) 0.55 (0.32–0.92)

Metastatic treatment 9.9 (9.2–11.2) 3.9 (3.5–5.6) 0.43 (0.32–0.57) Previous chemotherapy 0.22 Neoadjuvant or adjuvant treatment only

11.0 (7.6–NE) 5.6 (3.5–9.3) 0.60 (0.40–0.88)

Metastatic treatment 7.7 (5.7–9.5) 3.5 (1.9–5.4) 0.43 (0.29–0.64) None 10.8 (9.5–NE) 5.4 (3.4–7.3) 0.31 (0.18–0.53) PIK3CA status 0.83 Positive 9.5 (5.7–11.2) 3.6 (1.9–5.6) 0.48 (0.30–0.78) Negative 9.9 (9.2–13.9) 4.6 (3.4–7.3) 0.45 (0.31–0.64) Overall 9.5 (9.2–11.0) 4.6 (3.5–5.6) 0.46 (0.36–0.59)

Favours palbociclib

plus fulvestrant

Favours placebo

plus fulvestrant

0.125 0.25 0.5 1 2 4 8

ESR1 positive

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

PFS

(%

)

Time (months)

Palbociclib + Fulvestrant median PFS 9.4 mo (95% CI: 4.1–11.2)

Placebo + Fulvestrant median PFS 4.1 mo (95% CI: 2.8–5.6)

HR 0.524 (95% CI: 0.32–0.87) P=0.0052

67 65 49 47 39 38 35 35 23 22 10 9 1 1 0

39 37 27 25 19 18 11 11 5 5 2 1 1 1 0

Palbociclib + Fulvestrant


Number at risk:

ESR1 negative

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 P

FS (

%)

Time (months)

Palbociclib + Fulvestrant median PFS 9.5 mo (95% CI: 9.2–13.9)

Placebo + Fulvestrant median PFS 3.8 mo (95% CI: 3.4–7.4)

HR 0.438 (95% CI: 0.31–0.62) P<0.0001

198 190 164 158 146 146 121 119 56 54 19 12 5 5 0

91 87 56 54 40 40 32 31 14 14 9 5 0

Palbociclib + Fulvestrant


Number at risk:

PFS=progression-free survival. March 2015 final PFS data cut, Cristofanilli et al. Lancet Oncol, 2015.

Interaction P-values

P=0.1772 P=0.4877

PALOMA 3: PFS by ESR1 Mutation Status

Grade 1/2, %

Grade 3, %

Grade 4, %

Neutropenia 14 56 10

Fatigue 35 2 0

Leukopenia 14 24 1

Most common AE in the palbociclib arm was neutropenia

Febrile neutropenia was seen only with PAL + LET (1.6%)

Permanent discontinuation due to AEs was 9.7% (PAL + LET) vs 5.9% (PBO + LET)

Adverse Event ≥5% in Either Arm, %

Ribociclib + Letrozole n=334

Placebo + Letrozole n=330

All Grade 3 Grade 4 All Grade 3 Grade 4

Neutropenia 74 50 9.6 5.2 0.9 0

Leukopenia 33 20 1.2 3.9 0.6 0

Anemia 19 0.9 0.3 4.5 1.2 0

Lymphopenia 11 5.7 1.2 2.1 0.9 0

Thrombocytopenia 9.0 0.6 0 0.6 0 0

PALOMA 2

MONALEESA 2

(TODOS GRADOS)

PALOMA 2 PALOMA 3 MONALEESA 2 MONARCH 1 IB

P+L L P+F F R+L L A A

Fatiga 37,4 27,5 39 28 36,5 30 65,5 -

Mucositis 15,3 5,9 11,6 2,3 - - - 9

Alopecia 32,1 15,8 14,8 5,8 33,2 15,5 5,2 9,3

Naúseas 37,4 27,5 29 26 51,5 28,5 64,4 45,5

Vómitos 15,5 16,7 14,5 12,2 29 15 34,8 27,1

Rash 14 1 17,8 11,7 - - - 7,2

Hiporexia 14,9 9 12,8 7,6 18,6 15,2 45,5 23,9

Disgeusia - - 10,1 5 17,1 7,9 - 8,2

ALT - - 6 3 15,6 3,9 - -

AST - - 7 5 15 3,6 - -

Diarrea 26,1 19,4 19 18 35 22 90 70

Dolor abdom.

- - 8 6 - - 35 14,3

Creatinina - - - - - - 98 14

QTc - - <1 - 3,3 - - -

Tratamiento hormonal de > 2ª línea: Mediana PFS (m)

CONFIRM BELLE 2 (ctDNA mut)

BOLERO 2 PALOMA 3

Fulv 250

Fulv 500

Fulv Fulv + Buparl

.

Exem Exem. +

Everol.

Fulvest Fulvest +

Palbo

5,5 6,5 3,2 7 3,2 7,8 4,6 9,5

Post-progresión a CDK4/6 inh?

Post-progression Treatment Following Discontinuation of PALOMA-3 Study Treatment: Sites of Disease Progression

• In both treatment groups, the most common sites of disease progression were liver and bone

• One patient in each treatment group (<1% of the total study population) developed new brain metastases

Total (N=521)

PAL + FUL (n=347) PCB + FUL

(n=174)

Disease progression, n (%)

328 (63.0) 198 (57.1) 130 (74.7)

Most common sites of disease progression, n (%)*

Liver 243 (74.1) 149 (75.3) 94 (72.3)

Bone 98 (29.9) 55 (27.8) 43 (33.1)

Received post-progression systemic therapy, n (%)†

290 (88.4) 172 (86.9) 118 (90.8)

*Total number of patients with disease progression were used as the denominator for percentages. Patients could be counted more than once across disease sites. †Patients are counted for each type of therapy received as the first subsequent therapy starting on the same day. FUL, fulvestrant; PAL, palbociclib; PCB, placebo

Turner NC, et al. Poster presented at SABCS 2016 (Abstract P4-22-06)

• The median times* until the start of subsequent follow-up treatment were longer in the palbociclib plus fulvestrant group

• 193/290 patients who progressed on study discontinued their immediately subsequent line of therapy

– A smaller proportion of patients in the palbociclib plus fulvestrant group discontinued next-line treatment compared with the placebo plus fulvestrant group (32.6% vs 46.0%)

*Determined using the Kaplan-Meier method.

CI, confidence interval; FUL, fulvestrant;

PAL, palbociclib; PCB, placebo

Palbociclib + Fulvestrant had No Effect on the Therapeutic Benefit Derived from Subsequent

Treatments

Turner NC, et al. Poster presented at SABCS 2016 (Abstract P4-22-06)

Time from first dose to end of study treatment

n=142 PAL+FUL

6.9 (5.4–7.8)

All therapies

4.3 (3.5–5.6)

n=107 PCB+FUL

3.7 (2.8–4.6)

All therapies

5.7 (4.1–8.9)

n=124 PAL+FUL

6.1 (4.6–7.5)

Chemotherapy

4.8 (3.7–6.0)

n=88 PCB+FUL

3.7 (2.3–4.0)

Chemotherapy

5.9 (3.9–8.9)

n=57 PAL+FUL

7.6 (4.2–9.9)

Endocrine therapy

3.4 (2.4–6.1)

n=47 PCB+FUL

4.2 (2.8–5.6)

Endocrine therapy

4.4 (2.8–6.2)

n=44 PAL+FUL

7.1 (3.6–9.9)

Targeted therapy

3.4 (2.4–6.8)

n=42 PCB+FUL

4.0 (3.5–5.6)

Targeted therapy

5.0 (2.8–13.1)

Median time (95% CI), months

Time from start to end of the immediate follow-up therapy

CONCLUSIONES

• Primera línea - Rol para IA monoterapia? - Fulvestrant 500 mg (FALCON) (ESMO 2016) en pacientes no pretratadas ¿enf. no visceral? - Combinación fulvestrant + IA (SO226) (NEJM 2012) ? - IA + inhibidor CDK4/6. PALOMA 2 (ASCO 2016); Monaleesa 2 (ESMO 2016)

• Líneas sucesivas

- Fulvestrant parece ser más eficaz en primera línea (aprox. 16,5 vs 6 m) - Combinación de fulvestrant + inhibidor CDK4/6 (PALOMA 3) (Cristofanilli 2016) - Combinación de exemestano + everolimus (BOLERO 2) (Baselga 2012)

• No hay datos de la secuencia óptima - Similar eficacia - Elegir en base a toxicidad y tratamiento previo

• Qué paciente necesita la combinación y qué paciente es candidato a monoterapia?

- No se puede seleccionar por subgrupos clínicos ni moleculares - Sensibilidad hormonal? Mts no viscerales? - Biomarcadores

- ESR1 mutaciones, PI3K (ctDNA) - expresión génica (PAM 50) - Rb, p16, ciclina D1

CONCLUSIONES

CDK4/6 inh

Próximos estudios fase II rando. o fase III

1ª Línea: • PARSIFAL: Palbociclib + Fulvestrant vs letrozol 1ªL • MONARCH 3: Letrozol +/- Abemaciclib • MONALEESA3: Fulvestrant +/- Ribociclib • MONALEESA7: (pre-) Tam o GnRh-a + IA +/- Ribociclib • COMPLEEMENT: Letrozol + Ribociclib (+ GnRh-a si pre-) • X2107: Ribociclib + Alpelisib + Letrozol

Pretratados IA: • PEARL: Exemestano / Fulv + Palbociclib vs Capecitabina • SOLAR1: Fulvestrant +/- Alpelisib • SANDPIPER: Fulvestrant +/- Taselisib • MONARCH 2: Fulvestrant +/- Abemaciclib • nexMONARCH: Abema (2 dosis) +/- Tam • MONALEESA3: Fulvestrant +/- Ribociclib • X2108: Ribociclib + Alpelisib/Buparlisib + Fulvestrant • PIPA: Palbociclib + PI3K inh +/- Fulvestrant

Pretratados CDK4/6 inh: • BYLIEVE: (PI3k mut) Alpelisib + Fulv o IA

estrategias terapeúticas actuales y futuras en cáncer de mama … · fulvestrant 500 mg...

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