recommended management for er - oncologypro...first3 fulvelstrant 23.4 54.1 anastrozol 13 48.4 lea4...
TRANSCRIPT
Recommended management for ER Positive Advanced Breast Cancer
Sandra Ximena Franco, MD
Hematología Oncología
Directora, Centro de Oncología/ Clínica de Seno
Clínica del Country
Lima, Abril 4, 2019
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Conflicts of interest
• Clinical Research : Pfizer, Roche, Novartis, Merck y Abbvie,PUMA
• Advisory boards: Pfizer, Roche y Novartis, Astra-Zeneca
• Speaker events: Roche, Novartis, Pfizer, Astra-Zeneca,
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Molecular portraits of human breast tumors: Luminal Subtype
Perou CM et al, Nature 406:747,2000; Cancer Genome Atlas doi:10.1038/nature11412
The intrinsic subtype classification
Luminal A Luminal B
Frequence 35-40% 25-30%
ER expression +++ ++
PR expression +++ +
GATA3 expression +++ ++
Ki67 expression low (<14%) moderate(>14%)
)PI3K mutations 43% 29%
GATA3 mutations 14% 15%
HER2 amplification no 30%
Tp53 mutations 12% 29%
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Prognosis according to molecular subtype
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Genomic landscape varies among subtypes of breast cancer (N=510)
Network CGA: Comprehensive molecular portraits of human breast tumours. Nature 2012, 490:61–70.
PI3CA 36%, TP53 37%, GATA3 11%, all others <10%5t
h ESO-E
SMO L
atin
Amer
ican
Mas
terc
lass i
n Clin
ical O
ncolo
gy
The tumor profile may evolve over time and in response to treatment
Reprinted from Arnedos, M. et al., Nat Rev Clin Oncol. 2015 Jul 21. doi: 10.1038/nrclinonc.2015.123. [Epub ahead of print].Aurilio G, et al., EJC. 2014;50:277-289.
As tumors evolve, tumor profile in metastases does not necessary correlate to the one in primary tumor
Changes in ER status of ~20-33% and in HER2 of ~5-8% depending on the series
Oncogenesis
Cancer
Residual disease
Residual lethal disease
Treatment resistance
Treatment Recurrence
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Mutational landscape of ER+ MBC at progression
San Antonio Breast Cancer Symposium –December 6-10, 2016
This presentation is the intellectual property of Ofir Cohen. Contact them at([email protected]) for permission to reprint and/or distribute.
N=141Significant genes with SNV and indel alterations
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Changes in hormonal and HER-2 receptors in primary tumor and metastatic biopsies: A metanalysis
Aurilio G, et al., Acta Oncol. 2013;52:1649-1656;
Aurilio G, et al., EJC. 2014;50:277-289.
48 articles (mostly retrospective studies) – ER (33 articles, 4200 patients) – PR (24 articles, 2739 patients)– HER2 (31 articles, 2987 patients)
ReceptorPooled
Discordances (95% CI)
Positive to Negative
Negative toPositive
ER 20% (16-35) 24% 14% (P = 0.018)
PR 33% (29-38) 46% 15% (P < 0.0001)
HER2 8% (6-10) 13% 5% (P = 0.0004)
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Conventional approach to ER-positive/HER2-negative MBC
HORMONES
response
CHEMOTHERAPY
3RD LINE CHEMO
2ND LINE CHEMO
no response
Bone, soft tissue diseaseLow burden visceral diseaseLong disease-free interval“Hormonosensitive” disease
Visceral crisis
High tumor burden
Relevant symptoms
Need for a rapid response
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Guías internacionales de tratamiento del cáncer de mama metastásico RH+/HER2- enfatizan el uso de terapia endocrina
Recomendaciones ASCO1
Terapia endocrina en lugar de quimioterapia debe ser ofrecido como estándar de tratamiento de primera línea en pacientes con cáncer de mama metastásico, receptor hormonal positivo, excepto para la enfermedad que amenaza la vida o en la que hay dudas sobre la resistencia endocrina.
• El mayor beneficio es menor toxicidad y mejor calidad de vida para las pacientes, asociado con terapia endocrina comparado con quimioterapia. (Beneficio potencial: alto). El daño potencial es que la enfermedad metastásica progrese rápidamente y pueda ser fatal si no hay respuesta; sin embargo, este riesgo es bajo (Riesgo potencial de daño: bajo)
Recomendaciones ESMO/ABC2 2
Las guías de ESMO refuerzan el uso preferente de la terapia endocrina, inclusive en presencia de metástasis viscerales para el tratamiento del cáncer de mama RE +/HER2-. La quimioterapia debe ser reservada para los casos con enfermedad rápidamente progresiva o que se haya probado resistencia endocrina.
Recomendaciones NCCN3
Mujeres con cáncer metastásico o recurrente, con tumores; caracterizado por ser RE y/o RP positivos son candidatas apropiadas para iniciar terapia endocrina.
Menor toxicidad
Mejor calidad de vida
RH, receptor hormonal; RP, receptor de progesterona; RE, receptor de estrógenos; HER2, receptor 2 del factor de crecimiento epidérmico humano.
1. Partridge AH, et al. J Clin Oncol 2014;32:3307–3329;2. Cardoso F, et al. The Breast 2014;23:489–502;3. NCCN Guidelines: Breast Cancer. Version 3.2015.
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Analysis Nº ER+/ HER2–
First-Line Treatment for ABC Number of ET LinesBefore First CT
QT TE 1a línea 2a línea ≥3a línea
USA1 19,120 40% 60% 44% 12% 4%
Europa2 355 31% 69% 62% 7% 0%
Brasil3 690 53% 47% - - -
UK 209 50% 50% - - -
How Are Physicians Treating ER+/HER2–?
• La evidencia de estos estudios sugiere que el uso de líneas TH múltiples es bajo y posiblemente subóptimo entre pacientes estadounidenses / europeos / brasileños con CMMA ER+ / HER2-
• Una justificación puede ser la baja actividad mostrada por las terapias endocrinas clásicas en la progresión a IANE
CMA, cáncer de mama avanzado; QT, quimioterapia; TE, Terapia endocrina; TH, Terapia hormonal; IANE, Inhibidor de aromatasa no esteroideo.
1. Swallow E, et al. Curr Med Res Opin 2014;30:1537–1545; 2. Andre F, et al. Curr Med Res Opin 2014;30:1007–1016.3. Barrios CH, et al. Can Res. 2016;76, P06,-16,-04.4. Kurosky S, et al. Presented at the International Society for Pharmacoeconomics and Outcomes Research 18th Annual European Congress, 2015; Milan, Italy (PCN352)
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
AnálisisNº ER+/ HER2–
Tratamiento de primera línea para CMA
Número de líneas de TE antes de la primera QT
QT TE 1a línea 2a línea ≥3a línea
EUA1 19,120 40% 60% 44% 12% 4%
Europa2 355 31% 69% 62% 7% 0%
Brasil3 690 53% 47% - - -
RU4 209 50% 50% - - -
How Are Physicians Treating ER+/HER2–?
• La evidencia de estos estudios sugiere que el uso de líneas TH múltiples es bajo y posiblemente subóptimo entre pacientes estadounidenses / europeos / brasileños con CMMA ER+ / HER2-
• Una justificación puede ser la baja actividad mostrada por las terapias endocrinas clásicas en la progresión a IANE
CMA, cáncer de mama avanzado; QT, quimioterapia; TE, Terapia endocrina; TH, Terapia hormonal; IANE, Inhibidor de aromatasa no esteroideo.
Front-line endocrine therapy is chosen for 60%–70% of ER+ ABC patients
Fewer than 1 out of 4 (25%) treated with front-line ET continue on a second endocrine option.
1. Swallow E, et al. Curr Med Res Opin 2014;30:1537–1545; 2. Andre F, et al. Curr Med Res Opin 2014;30:1007–1016.3. Barrios CH, et al. Can Res. 2016;76, P06,-16,-04.4. Kurosky S, et al. Presented at the International Society for Pharmacoeconomics and Outcomes Research 18th Annual European Congress, 2015; Milan, Italy (PCN352)
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
First line therapy
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Efficacy of chemotherapy in TTP of disease
Response (%) Median TP (months)
Overall Survival
(Months)
Paclitaxel1 34% 6.0 22.2
Doxorrubicina1 36% 5.9 20.1
Paclitaxel / doxorrubicina1
47% 8.0 22.4
Docetaxel/
capecitabina2
42% 6.1 14.5
Gemcitabina / paclitaxel3
40.8% 5.2 18.5
TP, Tiempo hasta la progresión.
1.Sledge G.W, et al. Journal of Clinical Oncology. 2003;21:588-5922.O’Shaughnessy et al. Clin Oncol. 2002; 20(12):2812-2823.3. Biganzoli L, et al. European Oncological Disease, 2007;1(2):52-3
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Exemestano1 Anastrozol2 Letrozol3
Núm. de pacientes 190 vs. 192 340 vs. 328 458 vs. 458
Tasa de respuesta % 45 vs. 30 33 vs. 33 32 vs. 21
Beneficio clínico % 57 vs. 49 56 vs. 56 50 vs. 38
TP (meses) 10 vs. 6 8 vs. 8 9 vs. 6
SG (meses) --- 40 vs. 40 34 vs. 30
1.Paridaens R, et al. 4th EBCC,2004.
2.Bonneterre J, et al. JCO 2000;18:3748-3757.
3. Mouridsen H, et al. JCO . 2003;21:2101-9
Inhibidores de aromatasa versus tamoxifenocomo terapia hormonal de primera línea
TP, Tiempo hasta la progresión; SG, Sobrevida global
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
PFS and OS in recent phase III trials of first line hormonal therapy for ER-positive/HER2-negative ABC
Estudio Experimental arm PFS(months)
OS(months)
Control arm PFS (months)
OS (months)
FACT1 Anastrozol + Fulvestrant 10.8 37.8 Anastrozol 10.2 38.2
SWOG2262 Anastrozol + Fulvestrant 15.0 47.7 Anastrozol 13.5 41.3
FIRST3 Fulvelstrant 23.4 54.1 Anastrozol 13 48.4
LEA4 Letrozol o fulvestrant +Bevacizumab
19.3 52.1 Letrozol o fulvestrant
14.4 51.8
CALGB 405035 Letrozol+ Bevacizumab 20.2 47.2 Letrozol 15.6 43.9
PALOMA 26 Letrozol +Palbociclib 24.8 ND Letrozol 14.5 ND
FALCON7 Fulvestrant 16.6 ND Anastrozol 13.8 ND
CMA, cáncer de mama avanzado; SLP, supervivencia libre de progresión; SG, sobrevida global; ND, no disponible.
1. Bergh J et al., J Clin Oncol 2012; 2. Mehta RS et al., NEJM 2012; 3. Robertson JFR et al., JCO 2012; 4. Martin M et al., JCO 2015;5. Dickler M et al, JCO 2016; 6. Finn et al., ASCO 2015 ;6. Finn R. S, et al. N Engl J Med 2016;375:1925-36. 7. Robertson, et al. Lancet . 2016; 388: 2997–3005
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Combination anastrozole and fulvestrant in metastatic breast
cancer
Mehta RS et al, N Engl J Med 367:435, 2012. Bergh J et al, J Clin Oncol 30:1919,2012
SWOG FACT
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Mehta et al1 Bergh et al2
Patient characteristics: Prior adjuvant hormones Prior adjuvant chemotherapy
40%33%
68%*46%**
Median progression-free survival(anastrozol arm)
13.5 mo. 10.2 mo.
Fulvestrant plus anastrozol versus anastrozol: patient,
treatment and tumor characteristics
1 N Engl J Med 2012;367:435; 2 J Clin Oncol 30:1919,2012
*70% relative increase
**28% relative increase
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Fulvestrant plus anastrozol versus anastrozol : Overall survival
• N
NEJM, Metha et al, march 2019
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
CONFIRM Study: Overall Survival (final analysis at 75% of events)
0.1
0
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80
Fulvestrant 500 mg
Fulvestrant 250 mg
362 333 288 254 227 202 178 163 141 123 114 98 81 64 47 30 26 15 8 1 0500 mg
374 338 299 261 223 191 164 137 112 96 87 74 64 48 37 22 14 8 3 2 0250 mg
Time (months)
Pro
po
rtio
n o
f p
ati
en
ts a
live
Patients at risk:
Tick marks indicate censored observations. Time to censoring was similar between the treatment arms
aNominal value, cannot be claimed as significant
as no adjustments were made for multiplicity
Median TTD (months)
Fulvestrant 500 mg 26.4
Fulvestrant 250 mg 22.3
HR = 0.81; 95% CI: 0.69, 0.96; p=0.016a
Di Leo A et al. Cancer Research 2012, 72 (24 Suppl. 3) ; Abs S1-4
Di Leo A, et al. 2012 CTRC-AACR SABCS; Dec 5, 2012; General Session 1. http://sabcs12.m2usa.com/sabcsdsv.html
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study*
(full analysis set)
0
0.0
0.2
0.4
0.6
0.8
1.0
102 74 65 52 45 34 20 6103 69 55 39 30 21 8 2
Patients at risk:Time (months)
6 12 18 24 30 36 48
Proportion
of patients
alive and
progression-freeHR = 0.66; 95% CI: 0.47, 0.92;
p=0.01
Fulvestrant 500 mgAnastrozole 1 mg
Anastrozole 1 mg
Fulvestrant 500 mg
42
00
Robertson JFR et al. Breast Cancer Res Treat 2012; 136(2): 503-11
*Fulvestrant is not approved in this population5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Progression
Fulvestrant + placebo to Anastrozole
Fulvestrant (500 mg/day i.m.) days 0, 14
& 28 then every 28 days
+ placebo to Anastrozole (1 mg/day p.o.)
Survival
Postmenopausal women with ER+ve and/or PgR+ve locally advanced or
metastatic breast cancer not previously treated with any hormonal therapy
Progression
Survival
Anastrozole + placebo to Fulvestrant
Anastrozole (1 mg/day p.o.)
+ placebo to Fulvestrant (500 mg/day i.m.)
days 0, 14 & 28 then every 28 days
FALCON Study Design
PFS analysis at 306
progression events
OS analysis at 50%
La indicación aprobada para Colombia de Faslodex es en mujeres posmenopáusicas con Ca de mama avanzado local o metastásico, RE+, que presentan una recidiva durante o después del tratamiento antiestrogénico adyuvante o bien una progresión dela enfermedad durante el tratamiento con un antiestrógeno.
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
FALCON: PRIMARY ENDPOINT PFS
A circle represents a censored observation
HR 0.797 (95% CI 0.637, 0.999); p=0.0486
Median PFSFulvestrant: 16.6 monthsAnastrozole: 13.8 months
Number of patients at risk:FulvestrantAnastrozole
230232
187194
171162
150139
124120
110102
9684
8160
6345
4431
2422
1110
20
00
Pro
po
rtio
n o
f p
atie
nts
aliv
e an
d
pro
gres
sio
n f
ree
Time (months)
0.9
1.0
0.7
0.8
0.5
0.6
0.3
0.4
0.1
0.00 3 6 9 12 15 18 21 24 27 30 3633 39
0.2
Fulvestrant (n=230)
Anastrozole (n=232)
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
FALCON: PFS IN PATIENTS WITH OR WITHOUT VISCERAL DISEASE
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 monthsAnastrozole: 13.8 months
Pro
po
rtio
n o
f p
atie
nts
aliv
e a
nd
pro
gre
ssio
n-f
ree
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 a
nd
pro
gre
ssio
n-f
ree
Time (months)
0.9
1.0
0.7
0.8
0.5
0.6
0.3
0.4
0.1
0.00 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 monthsAnastrozole: 15.9 months
Fulvestrant (n=135) Anastrozole (n=119)
Fulvestrant (n=95) Anastrozole (n=113)
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Checkpoint G1/S REGULATION
Lange CA, Yee D. Endocr Relat Cancer 2011;18:C19–24
AR, receptor andrógeno; ER, receptor estrogénico; MAPK, proteínas kinasas activadas por mitógeno; NF-κB, factor nuclear kappa de cadena ligera potenciador de células B activadas; PI3K, kinasa fosfoinositido; PR, receptor de progsterona; R, punto de restricción; RB, retinoblastoma; STAT, activador de transcripción (todos por sus siglas en inglés)
RB
RB
Trancripciónde genesG2 S
M
G1
G0
PP P
P
Inactivo
Supresortumoral activo
E2F
E2F
R
CDK4/6Ciclina D
Pl3K/Akt
STATs MAPKs
(ER/PR/AR) Wnt/β-catenina
NF-κB
p16
p21
p53
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
PALOMA-1 / TRIO-18: Diseño del estudio (NCT00721409)
Estudio fase II aleatorizado, abierto, con la participación de 50 centros en 12 países.
Principales criterios de elegibilidad: enfermedad localmente recurrente, inoperable RE-positivo / HER2 negativo, postmenopáusicas, sin terapia previa para cáncer de mama avanzado, sin inhibidores CDK previos, sin letrozol en los últimos 12 meses, sin metástasis cerebrales previas/presentes, enfermedad medible (RECIST 1.0) o sólo enfermedad ósea, estado funcional ECOG ≤1, función medular ósea y renal adecuadas.
Palbociclib 125 mg/d† + Letrozol 2.5
mg/d
Letrozol 2.5 mg/d
Cáncer de mama
avanzado RE+/HER2-
1:1
A
L
E
A
T
O
R
I
Z
A
C
I
Ó
N
*
Palbociclib 125 mg/d† + Letrozol 2.5
mg/d
Letrozol 2.5 mg/d
Cáncer de mama avanzado
RE+/HER2- con amplificación
CCND1 y/o pérdida de p16
1:1
n=66 n=99
A
L
E
A
T
O
R
I
Z
A
C
I
Ó
N
*
Cohorte 1 Cohorte 2
Finn, et al. Lancet Oncol. E-pub Dec 16, 2014.
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
PALOMA-1/TRIO 18: PFS (ITT Population): Combined Cohorts
HR, hazard ratio; LET, letrozole; PAL, palbociclib
Finn RS, et al. Lancet Oncol 2015;16:25–35
PAL + LET(N=84)
LET(N=81)
No. of events (%) 41 (49) 59 (73)
Median PFS, months(95% CI)
20.2(13.8−27.5)
10.2(5.7−12.6)
HR(95% CI)
0.488(0.319−0.748)
P value 0.0004
100
81 48 36 28 19 14 6 3 3 1LET
90
80
70
60
50
40
30
20
10
0
PFS
pro
bab
ility
(%
)
0 4 8 12 16 20 24 28 32 36 40
Time (months)
84 67 60 47 36 28 21 13 8 5 1PAL + LETNo. of patients at risk
Palbociclib + letrozoleLetrozole
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
PALOMA-1/TRIO 18: PFS (ITT Population): Cohort 1 and Cohort 2
Cohort 1: ER+/HER2− ABC
Cohort 2: ER+/HER2− ABC with CCDN1 amplification and/or loss of P16
CCND1, cyclin D1; HR, hazard ratio; LET, letrozole; NE, not estimable; PAL, palbociclibFinn RS, et al. Lancet Oncol 2015;16:25–35
Cohort 1 PAL + LET
(N=34)LET
(N=32)
No. of events (%) 15 (44) 25 (78)
Median PFS, months(95% CI)
26.1(11.2−NE)
5.7(2.6−10.5)
HR(95% CI)
0.299(0.156−0.572)
P value <0.0001
Cohort 2PAL + LET
(N=50)LET
(N=49)
No. of events (%) 26 (52) 34 (69)
Median PFS, months(95% CI)
18.1(13.1−27.5)
11.1(7.1−16.4)
HR(95% CI)
0.508(0.303−0.853)
P value 0.0046100 100
PFS
pro
bab
ility
(%)
90
80
70
60
50
40
30
20
10
00 4 8 12 16 20 24 28 32 36 40
PFS
pro
bab
ility
(%)
90
80
70
60
50
40
30
20
10
00 4 8 12 16 20 24 28 32 36 40
Time (months) Time (months)
34 26 23 18 15 13 11 8 8 5 1 50 41 37 29 21 15 10 5
32 15 10 8 5 4 4 3 3 1 49 33 26 20 14 10 2
PAL + LET
LET
No. of patients at risk
Palbociclib + letrozole
Letrozole
Cohort 1: ER+/HER2− ABCCohort 2: ER+/HER2− ABC with CCDN1
amplification and/or loss of P16
Letrozole
Palbociclib + letrozole
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
30
Final OS Analysis: ITT Population• The addition of palbociclib led to a 3-month increase in OS
Data cutoff December 30, 2016Median duration of follow-up 64.7 months (95% CI: 58.8–73.0)
CI, confidence interval; HR, hazard ratio; ITT, intention-to-treat; LET, letrozole; OS, overall survival; PAL, palbociclib
Finn RS, et al. Presented at ASCO 2017 (Abstract 1001)
PAL + LET(n=84)
LET(n=81)
No. of patients at risk (%) 60 (71) 56 (69)
Median (95% CI) OS, months 37.5(31.4–47.8)
34.5(27.4–42.6)
HR (95% CI) 0.897 (0.623–1.294)
P value 0.281
Time (months)
0 12 24 84
OS
pro
bab
ility
(%
)
0
20
40
60
80
100
No. of patients at risk
LET
PAL + LET
36 48 60 72
84
81
73
67
63
52
–
–
38
33
28
21
13
10
8
3
PAL + LET
LET
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
PALOMA-2: Study Design (1008)1
1. 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 treatment for advanced disease
• AI-resistant patients excluded
RA
ND
OM
IZA
TIO
N
N=666a
2:1
Primary endpointInvestigator-assessed PFS
Secondary endpointsResponse, OS, safety, biomarkers, patient-reported outcomes
Stratification factors–Disease site (visceral, non-
visceral)–Disease-free interval (de novo
metastatic; ≤12 mo, >12 mo)–Prior (neo)adjuvant hormonal
therapy (yes, no)
• Statistical analysis designed to detect an increase in PFS with a true HR of 0.69 (representing a 31% improvement) with 347 events - 90% power with 1-sided α=0.025
Assumptions: Median PFS of placebo plus letrozole = 9 mos vs. palbociclib plus letrozole = 13 mos
• Blinded independent central review of efficacy endpoints performed as supportive analysis
aActual. AI=aromatase inhibitor; HER2=human epidermal growth factor receptor 2; OS=overall survival; PFS=progression-free survival; QD=once daily.5t
h ESO-E
SMO L
atin
Amer
ican
Mas
terc
lass i
n Clin
ical O
ncolo
gy
PALOMA-2: SLP evaluada por el investigador (Población IT)
Pro
bab
ilid
ad d
e SL
P (
%)
Tiempo desde la aleatorización (meses)
0 3 6 9 12 15 18 21 24 27 30 33
444 395 360 328 295 263 238 154 69 29 10 2222 171 148 131 116 98 81 54 22 12 4 2
PAL+LETPCB+LET
Número de pacientes en riesgo
Palbociclib + letrozol (n=444)
Placebo + letrozol (n=222)
0
10
20
30
40
50
60
70
80
90
100
PAL+LET (N=444) PCB+LET (N=222)
Número de eventos, n (%) 194 (44) 137 (62)
Mediana de SLP (IC 95%) 24.8 (22.1–NR) 14.5 (12.9–17.1)
CR (IC 95%); valor P en 1 cola 0.58 (0.46–0.72); P<0.000001
IT, Intención de tratar; LET, letrozol; NR, no alcanzada; PAL, palbociclib; PCB, placebo; SLP, supervivencia libre de progresión; CR, cociente de riesgo.
Finn, et al. N Engl J Med 2016, 17;375(20): 1925–1936.
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
MONALEESA-2
− Las evaluaciones tumorales se realizaron cada 8 semanas por 18 meses, posteriormente cada 12 semanas
− Análisis final planeado después de 302 eventos de supervivencia libre de progresión (SLP)• Poder de 93.5% para detectar una reducción del riesgo de 33% (CR 0.67) en una cola α=2.5%
− Análisis preliminar planeado después de ~70% de eventos de SLP (211 de 302 eventos)• Criterios de interrupción de Haybittle-Peto de dos vías: cociente de riesgo ≤0.56 y p ≤0.0000129
Aleatorización 1:1
Estratificado por la presencia/ausencia
de metástasis hepáticas y/o pulmonares
Ribociclib (600 mg/día)3 semanas en tx/1
semana sin tx+
Letrozol (2.5 mg/d)n=334
Placebo+
Letrozol (2.5 mg/d)n=334
Objetivo primario• SLP (evaluada localmente
por RECIST v1.1)
Objetivos secundarios• Sobrevida global
(principal)• Tasa de respuesta global• Tasa de beneficio clínico• Seguridad
• Mujeres postmenopáusicas con cáncer de mama avanzado RH+/HER2-
• Sin terapia previa para enfermedad avanzada
• N=668
MONALEESA-2: Estudio fase III, doble ciego, controlado con placebo de ribociclib + letrozol
RH, receptor hormonal; HER2, receptor 2 de factor de crecimiento epidérmico humano ; tx, tratamiento; CR, cociente de riesgo.
Hortobagyi, et al., N Engl J Med 2016, 375:1738-1748
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
MONALEESA-2: Progression-free Survival
Hortobagyi G, et al. ASCO 2017. 3. Hortobagyi G, et al. NEJM 2016.
MONALEESA-2 (ASCO 2017)(investigator assessed mPFS)
Blinded independent central review (BICR)
Ribo + LET PBO + LET
mPFS,months(95% CI)
25.3(23.0–30.3)
16.0(13.4–18.2)
HR (95% CI)
0.568(0.457–0.704)
p value 9.63 × 10-8
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
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)
Hortobagyi et al NEJM 2016
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
MONARCH 3: Study Design
Statistics: Study powered to 80% at one-sided alpha of 0.025 assuming a hazard ratio of 0.67 with analyses at 189 and 240 PFS events. Positive study at the interim required a hazard ratio <0.56 and two-sided p<0.0005
Enrollment: From November 2014 to November 2015 patients enrolled in 158 centers from 22 countries
Median follow-up: 17.8 months (interim analysis)
• HR+, HER2– ABC
• Postmenopausal
• Metastatic or locally recurrent disease with no prior systemic therapy in this setting
• If neoadjuvant or adjuvant ET administered, a disease free interval of >12 months since completion of ET
• ECOG PS ≤1
RA
ND
OM
IZAT
ION
2:1
N=493
abemaciclib: 150 mg BID(continuous schedule) plus
anastrozole: 1 mg or a
letrozole: 2.5 mg QD until PD
a Per physician’s choice: 79.1% received letrozole, 19.9% received anastrozole.
placebo: BID(continuous schedule) plus
anastrozole: 1 mg or a
letrozole: 2.5 mg QD until PD
Primary endpoint:
Investigator-assessed PFS
Secondary endpoint:
OS, Response rates, Safety
Stratification factors:
• Metastatic site (visceral, bone only, or other)
• Prior ET (AI, no ET, or other)
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Primary Endpoint (PFS) Met at Interim Analysis
PFS benefit confirmed by blinded independent central review: HR (95% CI): 0.508 (0.359, 0.723); p=0.000102
100P
rog
res
sio
n-f
ree
Su
rviv
al
(%) 90
80
70
60
50
40
30
20
10
0
0 4 8 12 16Time (months)
20 24 26
328165
abemaciclib armplacebo arm
Patients at Risk:
271127
234105
20582
12545
257
10
00
Median PFS
abemaciclib + NSAI: not reached
placebo + NSAI: 14.7 months
HR (95% CI): 0.543 (0.409, 0.723)
p=0.000021
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Efficacy of endocrine therapy in the first line setting in Breast Cáncer RH+ HER2-1,2,3
68,2
6 5,8
13,814,5
8,2 8,39,4
9,9
16,6
24,8
0
5
10
15
20
25
30
Sledge et al(Chemotherapy)
Bonneterre et al Mouridsen et al Paridaens et al FALCON PALOMA 2
Pal
bo
cicl
ib+L
etro
zol
1. Finn RS, Palbociclib and Letrozol in Advanced Breast Cancer. N Engl J Med. 2016 Nov 17;375(20):1925-19362. Robertson JF, Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016 Dec 17;388(10063):2997-30053. Kümler I, Knoop AS, Review of hormone-based treatments in postmenopausal patients with advanced breast cancer focusing on aromatase inhibitors and fulvestrant.
**S
LAm
/mT
TPen
mes
es
Pla
ceb
o+L
etro
zol
Pac
litax
el+D
oxo
Pac
litax
el
Exem
esta
no
Tam
oxi
fen
o
Letr
ozo
l
Tam
oxi
fen
o
Tam
oxi
fen
o
An
astr
azo
l
Fulv
estr
ant
An
astr
azo
l
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Adverse EventsFrequency of All Grade AEs (Gr3/4)
Ribociclib Palbociclib Abemaciclib
MONALEESA-2R + Letrozole (n=334)1
PALOMA-2P + Letrozole (n=444)2
MONARCH-3A + NSAI (n=328)
Neutropenia 74% (59%) 80% (66%) 41% (21%)
Anemia 19% (1%) 24% (5%) 28% (6%)
Leukopenia 33% (21%) 39% (25%) 21% (8%)
Nausea 52% (2%) 35% (<1%) 39% (1%)
Diarrhea 35% (1%) 26% (1%) 81% (10%)
Constipation 25% (1%) 19% (<1%)
Vomiting 29% (4%) 16% (<1%) 28% (1%)
Fatigue 37% (2%) 37% (2%) 40% (2%)
Headache 22% (<1%) 21% (<1%)
Alopecia 33% (0%) 33% (0%) 27% (0%)
Arthralgia 27% (1%) 33% (<1%)
Hot Flush 21% (<1%) 21% (0%)
Back Pain 20% (2%) 22% (1%)
Cough 20% (0%) 25% (0%)
Abdominal Pain 29% (1%)
Decreased Appetite 19% (2%) 15% (1%) 25% (1%)
Venous thromboembolic event NR* NR** 4.9%
1. Hortobagyi et al. NEJM 2016; 375: 1738-17482. Finn RS, et al. NEJM 2016; 375: 1925-1936.
He
mat
olo
gic
Sym
pto
mat
ic
*Thromboembolic events: 2.7% (0.9%); Pulmonary embolism: 1.2% (0.3%). **Pulmonary embolism: 0.9 %
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Progression after first line therapy/ resistance?
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Study Brazos del estudio DoR TP
0020/0021Fulvestrant / Anastrozol
16.7 m/13.7 m 5.5 m / 4.1 m
EFECT Fulvestrant / Exemestano
13.5 m / 9.8 m 3.7 m / 3.7 m
SoFEA Fulvestrant + Anastrozol /
Fulvestrant + Placebo/Exemestano
12.3 m / 17.2 m / 17.2 m
4.4 m / 4.8 m / 3.4 m
Fulvestrant 250: PHASE III STUDIES AFTER PROGRESSION FROM AI
DDR, duración de respuesta; TP, tiempo hasta la progresión; IA, inhibidores de aromatasa
Bergh J et al. JCO 2012;30-1919-1925.
Robertson et al. Cancer 2003.
Jonhston, et al. Lancet Oncol. 2013; 14: 989–98
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Mechanisms of resistance to hormones
•Loss of ER expression
•Truncated ER-ἁ / mutations of
ESR 1
• Alternative signaling (receptor
TK signaling):
•activation of PI3K pathway
•mTOR activation
•Postranscriptional activation:
•MYC mutations
•Overexpression of cyclines
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
PI3K/AKT/mTOR Pathway Inhibitors
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Crosstalk Between ER and PI3K/AKT/mTOR Signaling: Rationale for Dual Inhibition
• mTORC1 activates ER in a ligand-independent fashion1
• Hyperactivation of the PI3K/AKT/mTOR pathway is observed in endocrine-resistant breast cancer cells2due to1,2:
-Increased HER2-mediated signaling-Mutational inactivation or loss of
PTEN-Activating mutation or amplification of
PIK3CA
• mTOR is a rational target to enhance the efficacy of endocrine therapy
Abbreviations: AKT, protein kinase B; EGFR, epidermal growth factor receptor; ER, endocrine
receptor; ERE, endocrine response element;
HER2, human epidermal growth factor receptor-2; IGF-1R, insulin-like growth factor-1 receptor;
MAPK, mitogen-activated protein kinase;
mTOR, mammalian target of rapamycin; mTORC1, mTOR complex 1; PI3K,
phosphatidylinositol-3-kinase; PTEN, phosphatase and tensin.
1. Yamnik RL, et al. J Biol Chem. 2009;284(10):6361-6369; 2. Miller TW, et al. J
Clin Invest. 2010;120(7):2406-2413.
Adapted from Johnson SR. Clin Breast Cancer. 2009;9(suppl 1):S28-S36.
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Hormone therapy plus mTOR inhibitors in patients previously exposed to AI
TAMRAD BOLERO
CR, cociente de riesgo; IA, inhibidor de aromatasa; IC, Intervalo de confianza; SLP, Supervivencia libre de progresión.
Bachelot T et al., J Clin Oncol 2012;30:2718 Baselga J et al., N Engl J Med 2012;366:520
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
SLP: Valoración local
84
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54 60 66 72 78 90 96
Tiempo (semanas)
Pro
bab
ilid
ad (
%)
de
l Ev
en
to CR = 0.44 (IC del 95%, 0.36-0.53)Valor de P de Log rank: < 1 × 10-
16
EVE + EXE: 7.4 mesesPBO + EXE: 3.2 meses
EVE + EXE (E/N = 267/485)
PBO + EXE (E/N = 190/239)
Everolimus
Placebo
Número de pacientes que permanecen en riesgo
485 436 365 303 246 188 136 96 64 45 34 21 13 9 2 2 0
239 190 131 95 63 45 29 19 12 8 6 6 4 2 0 0 0
CR = 0.36 (IC del 95%, 0.28-0.45)Valor de P de Log rank: < 1 × 10-
16
EVE + EXE: 11.0 mesesPBO + EXE: 4.1 meses
SLP: Valoración central
Everolimus
Placebo
485 422 351 284 224 176 119 86 57 38 32 22 12 7 2 2 0
239 179 112 74 56 36 23 18 8 5 4 4 3 1 0 0 0
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Pro
bab
ilid
ad (
%)
de
l Ev
en
to
EVE + EXE (E/N = 155/485)
PBO + EXE (E/N = 127/239)
Tiempo (semanas)
CR, cociente de riesgo; SLP, Supervivencia libre de progresión; CI, intervalo de confianza.Yardley D et al. Adv Ther. 2013; 30(10):870-884.
BOLERO-2: Final Analysis of Progression-free Survival by Local and Central Assessment
Número de pacientes que permanecen en riesgo
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
BOLERO-2 (39-mo) Final Overall Survival Analysis
47
One-sided P value was obtained from the log-rank test stratified by sensitivity to prior hormonal therapy and presence of visceral metastasis from IXRS®.
Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; IXRS®, Interactive Voice and Web Response System; PBO, placebo.
Piccart M, et al. EBCC 2014. Abstract 1LBA.
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
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
PrECOG 0102: FUL + EVE or PBO in postmenopausal women with HR+, HER2– MBC resistant to AI therapy
• Objective: To evaluate the efficacy of FUL + EVE vs FUL + PBO in pts with HR+, HER2– AI-resistant MBC
• Methodology:
Kornblum et al. (Abstract #S1-02 – oral)
*FUL 500 mg administered on day 1 and 15 of cycle 1, then on day 1 of cycles 2-12 (28 days cycle)
Arm A & B (week 48)
Unblind and continueFUL ± EVE
Induction Phase (treat until progress or unacceptable toxicity. Maximum of 48 wks) Continuation Phase
If no PD or unacceptable toxicity
N=130• Postmenopausal women with HR+, HER2– MBC relapsed
on and/or resistant to prior AIs• ECOG PS 0-1• ≤ 1 prior chemotherapy regimen for metastasis• Measurable and/or non-measurable disease (RECIST 1.1)• 2 doses of FUL permitted within 28 days prior to
randomization
Arm A: FUL (500 mg)* +
EVE (10 mg) PO QD(n=66)
Arm B: FUL (500 mg)* +
PBO (PO QD)(n=65)
R1:1
EndpointsPrimary:• PFS (by investigator
assessment)Secondary: • Safety, OS, ORR and
TTP
Stratification factors: ECOG PS (0 vs 1), measurable disease, prior chemotherapy for
*1 Gr4 AE was reported and was not specified
Figure 2: Overall SurvivalFigure 1: Progression Free Survival (by investigator assessment – primary study endpoint)
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
PALOMA-3: Phase III Study Design
• Primary endpoint: investigator-assessed PFS
• Secondary endpoints: ORR, CBR (CR, PR, or SD for ≥ 24 wks), OS, pt-reported outcomes, safety
Pts with HR+/HER2-
MBC; PD after
endocrine therapy;
≤ 1 chemotherapy
regimen for
advanced BC
(N = 521)
Palbociclib 125 mg QD
3 wks on/1 wk off +
Fulvestrant 500 mg IM Q4W
(n = 347)Tx to PD, toxicity,
or study
withdrawal
Placebo 3 wks on/1 wk off +
Fulvestrant 500 mg IM Q4W
(n = 174)
Cristofanilli M, et al. SABCS 2015. Abstract P4-13-01.
Stratified by visceral
metastases (yes/no), sensitivity
to previous endocrine therapy,
menopausal status
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
347 333 281 273 247 244 202 197 91 85 32 023 7 7 1Palbociclib + fulvestrant
174 165 112 105 83 80 59 58 22 22 13 07 2 1 0Placebo + fulvestrant
No. at risk
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 1511 12 13 14
Placebo + fulvestrant
Palbociclib + fulvestrant
PALOMA-3 Final Analysis: Investigator-assessed PFS (ITT Population)
FUL, fulvestrant; HR, hazard ratio; PAL, palbociclib; PBO, placebo
Cristofanilli M, et al. Lancet Oncol 2016 2016 Apr;17(4):425–39
PAL + FUL(n=347)
PBO + FUL(n=174)
Median PFS, months (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
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Paloma 3: Overall survival
NEJM, Turner Oct. 2018
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Paloma 3: Overall survival
NEJM, Turner Oct. 2018
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
No. at risk
Ribociclib + fulvestrant
Placebo + fulvestrant
193
97
161
66
146
50
136
47
128
43
114
39
101
37
95
33
87
30
53
18
22
8
174
6
0
0
0
Pro
babilit
y o
f PFS (
%)
0 2 4 6 8 10 12 14 16 18 20 22 24 26
MONALESSA -3 Supportive analysis: PFS (Blinded Independent Review Committee*)
BIRC, Blinded Independent Review Committee; NR, not reached.
*Audit-based review of 40% of randomized patients.
Based on the prespecified thresholds to trigger a full BIRC review of all patients’ data, a full BIRC review was not required.
PFS (BIRC)Ribociclib + fulvestrant
n=193
Placebo + fulvestrant
n=97
Events, n (%) 72 (37.3) 54 (55.7)
Median PFS, months (95% CI)
NR(18.2–NR)
10.9(3.8–17.2)
Hazard ratio (95% CI) 0.492 (0.345–0.703)
Time (months)
100
80
60
40
20
0
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Pro
babilit
y o
f PFS (
%)
26222016121086420 1814 24
0
20
40
60
80
100
Time (months)
Pro
babilit
y o
f PFS (
%)
26181614121086420 20 22 24
0
20
40
60
80
100
Time (months)
MONALESSA 3:PFS by prior endocrine therapy status
5
4
First line* Second line + early relapsers‡
PFS (investigator assessment)
Ribociclib +fulvestrant
n=236
Placebo + fulvestrant
n=109
Events, n (%) 131 (55.5) 84 (77.1)
Median PFS, months
14.6 9.1
Hazard ratio (95% CI)
0.565 (0.428–0.744)
PFS (investigator assessment)
Ribociclib +fulvestrant
n=238
Placebo + fulvestrant
n=129
Events, n (%) 76 (31.9) 66 (51.2)
Median PFS, months
NR 18.3
Hazard ratio (95% CI)
0.577 (0.415–0.802)
No. at risk
Ribociclib +
fulvestrant
Placebo +
fulvestrant
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
No. at risk
Ribociclib +
fulvestrant
Placebo +
fulvestrant
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
*Treatment naive for ABC; ‡Received up to 1 line of prior endocrine therapy for ABC.
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Inhibición PI3K / AKT / mTOR en cáncer de mama
Inhibidores PI3K p110α► Alpelisib (BYL719)► Taselisib (GDC-0032)► MLN1117► GSK2636771
Inhibidores Pan-PI3K► Buparlisib (BKM120)► Pictilisib (GDC-0941)► XL147
Receptor de tirosina cinasa
S6K
PTEN
Factor de crecimiento (EGFR, FGFR, HER2 / 1, IGFR1)
PRAS40
mTORC1
mTORC2
4EBP1
eIF4E
p85
p110PI3K
TSC1/2
Rheb
Inhibidores de mTORC1► Everolimus► Ridaforolimus► Temsirolimus
Inhibidores de mTORC1/2► AZD2014► MLN0128► INK128► OSI-027
Inhibidores de AKT► Ipatasertib► AZD5363► GSK141795► MK2206► Perifosina
Akt
Zardavas D, et al. Nat Rev Clin Oncol. 2013;10(4):191-210.Slomovitz BM, et al. CCR. 2012;18(21): 5856-5645.
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Buparlisib (BKM120): A Potent Oral Pan-PI3K Inhibitor
• BKM120 is a potent oral pan-class I PI3K inhibitor that selectively inhibits all 4 class I PI3K isoforms (α,β,γ,δ)1,2
• Demonstrated antiproliferative and pro-apoptotic activity in 6 human tumor cell lines that model TRAS resistance (ie, dysregulated PI3K pathways)1
• Potent antitumor activity in tumor xenograft models2
• Phase 1 dose-escalation and expansion study completed3
• 26 registered trials of BKM120 (single-agent or in combination) in BC patients4
– Target enrollment > 4000 patients
1. Voliva CF, et al. AACR 2010, Abstr 4498 (poster); 2. Maira M, et al. Mol Cancer Ther 2011;11:317-328;
3. Rodon J, et al. Invest New Drugs. 2014; DOI: 10.1007/s10637-014-0082-9; 4. http://clinicaltrials.gov/ct2/results?term=BKM120%2C+breast+cancer&Search=Search
Reprinted from Rodon J, et al. SABCS 2011, Abstr P3-16-01 (poster). Based on data from Cully M, et al. Nat Rev Cancer. 2006;6(3):184-192.
56
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
TASELISIB (GDC0032)
Via
bil
ida
d d
e la
cé
lula
(Un
ida
de
s C
TG
)
Via
bil
ida
d d
e la
cé
lula
(Un
ida
de
s C
TG
)
Taselib:
Letrozol:Taselib:
Letrozol:
Hoeflich KP, et al., Genes & Cancer 2016;7.
Molécula pequeña que inhibe de forma selectiva las isoformas de la clase I PI3K
Muy potente para inhibir la isoforma PI3Kβ
Modelos preclínicos hay sinergia entre letrozol y taselisib
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
BYL719 A Specific Inhibitor of the p110α Catalytic Isoform of PI3K
• BYL719 is an α-isoform-specific inhibitor of class I PI3K1
• BYL719 inhibited p110α and p110α mutants (IC50=5 nM) and is selective (>50-fold) against a wide range of protein kinases.1
• In breast cancer cell lines harboringPI3KCA mutations, BYL719 inhibited the PI3K.
Gonzalez-Angulo et al. ASCO 2013, Abstract 2531.
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
PIK3CA mutations and alpelisib
– PI3K includes catalytic and regulatory subunits1,2
• There are 4 isoforms of the PI3K catalytic subunit; PIK3CA encodes the α-isoform1
• Around 40% of patients with HR+, HER2– breast cancer present an activating tumor mutation of PIK3CA3,4
– Pan-PI3K inhibitors target multiple isoforms of PI3K, leading to excess toxicities and marginal efficacy5–7
– Alpelisib (BYL719) is a specific inhibitor of the PI3K α-isoform8
– Alpelisib has demonstrated antitumor activity in preclinical models harboring PIK3CA alterations8
1. Engelman JA. Nat Rev Cancer 2009;9:550–562; 2. Janku F. Cancer Treat Rev 2017;59:93–101; 3. The Cancer Genome Atlas Network. Nature 2012;490:61–70; 4. Mollon L, et al. AACR 2018 (poster 2107). 5. Baselga J, et al. J Clin Oncol 2018;36 (Suppl): LBA 1006;6. Di Leo A, et al. Lancet Oncol 2018 19(1):87–100;
7. Baselga J, et al. Lancet Oncol 2017;18(7):904–916; 8. Fritsch C, et al. Mol Cancer Ther 2014;13:1117–1129.
There is a strong rationale for targeting the α-isoform of PI3K in patients with a PIK3CAmutation
Regulatory
subunit
Catalytic
subunit p110
p85
PI3K
PI3K
isoforms
α
β
γ
δ
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
SOLAR-1: A Phase III randomized, controlled trial (NCT02437318)
• *Fulvestrant given on Day 1 and Day 15 of the first 28-day cycle, then Day 1 of subsequent 28 day cycles.
Men or postmenopausal
women, with HR+,
HER2– ABC
• Recurrence/progression
on/after prior AI
• Identified PIK3CA status (in
archival or fresh tumor tissue)
• Measurable disease or
≥1 predominantly lytic
bone lesion
• ECOG performance status ≤1
(N=572)
1:1, stratified by presence of
liver/lung metastases and prior CDK4/6 inhibitor treatment
Primary endpoint
• PFS in PIK3CA-mutant cohort
(locally assessed)
Secondary endpoints include:
• OS (PIK3CA-mutant cohort)
• PFS (PIK3CA-non-mutant cohort)
• PFS (PIK3CA mutation in ctDNA)
• OS (PIK3CA-non-mutant cohort)
• ORR/CBR
• Safety
ALP 300 mg QD PO
+ FUL 500 mg IM*
n=169
PBO
+ FUL 500 mg IM*
n=172
R
PIK3CA-non-
mutant cohort
(n=231)
ALP 300 mg QD PO
+ FUL 500 mg IM*
n=115
PBO
+ FUL 500 mg IM*
n=116
R
PIK3CA-
mutant cohort
(n=341)
Andre,F; ESMO 2018
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Inclusion criteria: Prior exposure to AI
– Patients who had received one prior line of endocrine therapy were enrolled
• Endocrine resistance and endocrine sensitivity were defined according to the ESMO guidelines1
• Patients who had not received ET for ABC were considered “first line”
Relapse
(Neo)adjuvant ET
(Neo)Adjuvant ET
Dia
gn
osi
s
(Neo)Adjuvant ET
ET for advanced disease Progression
ET for advanced disease Progression
Relapse
Relapse Excluded after a protocol amendment
≤1 year
>1 year
>1 year
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Primary endpoint: Locally assessed PFS in the PIK3CA-
mutant cohort
– The primary endpoint crossed the prespecified Haybittle–Petoboundary (one-sided p≤0.0199)
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)
Progression 99 (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
Andre,F; ESMO 2018
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Proof of Concept: PFS in the PIK3CA-non-mutant cohort
Proof of concept criteria were not met in the PIK3CA-non-mutant cohort
– Proof of concept criteria: estimated hazard ratio ≤0.60 and posterior probability ≥90% that the hazard ratio was <1
– Patients with PIK3CA-non-mutant disease were followed up for safety alongside the PIK3CA-mutant cohort
•
Data cut-off:
Dec 23, 2016
Alpelisib +
fulvestrant
(N=115)
Placebo +
fulvestrant
(N=116)
Number of PFS events, n (%) 49 (42.6) 57 (49.1)
Progression 47 (40.9) 57 (49.1)
Death 2 (1.7) 0
Censored 66 (57.4) 59 (50.9)
Median PFS
(95% CI)
7.4
(5.4–9.3)
5.6
(3.9–9.1)
HR (95% CI) 0.85 (0.58–1.25)
Posterior probability
HR<1, %79.4
Andre,F; ESMO 2018
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
PFS by Prior CDK4/6 Inhibitor Treatment in the PIK3CA-mutant Cohorta
64ABC, advanced breast cancer; CI, confidence interval; ET, endocrine therapy; HR, hazard ratio; PFS, progression-free survival.a Mutation status determined from tissue biopsy.
This presentation is the intellectual property of Dejan Juric. Contact [email protected] for permission to reprint and/or distribute.
Without Prior CDK4/6 inhibitor therapy
ALP + FUL (n = 160)
PBO + FUL (n = 161)
Events, n (%) 96 (60.0) 119 (73.9)
Median PFS,
mo11.0 6.8
HR, (95% CI) 0.67 (0.51-0.87)
With Prior CDK4/6 inhibitor therapy
ALP + FUL (n = 9)
PBO + FUL (n = 11)
Events, n (%) 7 (77.8) 10 (90.9)
Median PFS, mo 5.5 1.8
HR, (95% CI) 0.48 (0.17-1.36)
• Previous treatment with any CDK4/6 inhibitor was a stratification factor, however the number of patients enrolled who had
received prior CDK4/6 inhibitor therapy was small
• Treatment benefit with alpelisib was observed regardless of prior use with a CDK4/6 inhibitor
Censoring times
Alpelisib + fulvestrant
Placebo + fulvestrant
0 1 2 3 4 5 6 7 8 9
Time (months)
Eve
nt-
fre
e p
rob
ab
ilit
y (
%)
10
100
80
60
40
20
0
11 12 13 14 15 16 17
Censoring times
Alpelisib + fulvestrant
Placebo + fulvestrant
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
Time (months)
Even
t-fr
ee p
rob
ab
ilit
y (
%)
100
80
60
40
20
0
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
ASCO Guidelines 2016
Rugo H, et al., J Clin Oncol 34:3069-3103
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Take home messages
Patients with ER+ ABC should be treated with hormone therapyexcept for those with a “visceral crisis” or those with alreadyproven resistance to endocrine therapy. There are many proventherapeutic options
Sequencing remains a challenge as most trials are not designed toanswer this question.
A better understanding of resistance mechanisms is needed (andthis will require new tissue or blood biopsies at progression).
Future efforts should identify more sensitive molecularly definedpopulations, allowing for more intelligent and personalizedtreatment.
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
ABC 3 RECOMMENDATIONS• We strongly recommend the use of objective scales, such as
the ESMO Magnitude of Clinical benefit or the ASCO ValueFramework to evaluate the real magnitude of benefitprovided by a new treatment and help prioritize funding, particularly in countries with limited resources
• Premenopausal women, usually not included in the trialsshould have adecuate ovarian supression or ablation and be treated the same as post menopausal women
• The addition of Everolimus to an AI is a valid option since itsignificantly improves PFS ( no OS benefit), taking intoaccount toxicities . It can be combined with tamoxifen orfulvestrant.
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
• The addition of a CDK 4/6 inhibitor to an AI in patientsnaive or pre exposed to endocrine therapy is one of thepreferred treatment options , it has an aceptable toxicity profile. Patients relapsing within 12 monthsfrom the end of adjuvant therapy were not included.
• We are still awaiting OS
• In patients previously exposed to ET, the addition of CDK4/6 inhibitor to fulvestrant is one of the preferredoptions if this drugs were not previously used
• OPTIMAL SEQUENCE is uncertain
ABC 3 RECOMMENDATIONS
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology
Thank you
5th
ESO-ESM
O Lat
in Am
erica
n M
aste
rclas
s in
Clinica
l Onc
ology