ASCO 2009 - Highlights

Individualizando el Cuidado del Cáncer

Conclusiones

Sarcoma
Sarcoma
Melanoma
Melanoma

Colon
Colon // Recto
Recto // Ano
Ano

GI
GI no
no colorrectal
colorrectal

Mama
Mama

Mauricio Lema Medina MD

 Cáncer de mama
50 años avanzando con la evidencia, y unos Manejo
Manejo Loco-Regional
Loco-Regional
pocos retrocediendo con el deseo...
Radioterapia post mastectomía en enfermedad N1
Disección ganglionar axilar en micrometástasis

Biomarcadores
Biomarcadores en
en cáncer
cáncer temprano
temprano
Chemo-N0: uPA/PAI-1
70-gene profile
Estudios
I-SPY-Trial
seleccionados E2197: Perfil genético en triple negativos
como los más
importantes Tratamiento
Tratamiento sistémico
sistémico enfermedad
enfermedad temprana
temprana
Cisplatino en mutaciones BRCA
Inhibidores de la CYP2D6 y tamoxifén
Disfunción cognitiva con Letrozol / Tamoxifén
Salud ósea e inhibición del RANKL

16 Estudios Cáncer
Cáncer de
de mama
mama avanzado
avanzado
RIBBON-1: Otro estudio con Bevacizumab
Doc/GemCap vs Doc/CapGem
T-DM1: Esperanza luego de Trastuzumab
La historia del PARP-1
Letalidad sintética
 Letalidad sintética

Letalidad resultante de la interacción

simultánea de factores no letales en
forma aislada
Iglehart, J. Dirk, Silver, Daniel P. Synthetic Lethality -- A New Direction in Cancer-Drug Development
N Engl J Med 2009 361: 189-191
Iglehart, J. Dirk, Silver, Daniel P. Synthetic Lethality -- A New Direction in Cancer-Drug Development
N Engl J Med 2009 361: 189-191
Iglehart, J. Dirk, Silver, Daniel P. Synthetic Lethality -- A New Direction in Cancer-Drug Development
N Engl J Med 2009 361: 189-191
Iglehart, J. Dirk, Silver, Daniel P. Synthetic Lethality -- A New Direction in Cancer-Drug Development
N Engl J Med 2009 361: 189-191
 Neoadjuvant Study: Design

S
BRCA1 mutation U
carriers, Cisplatin 75 mg/m2 R
G AC
primary breast q 3 wks IV x 4 cycles
cancer E
R
N = 10 25
Y
 Primary endpoint: pCR (in breast and axilla, DCIS permitted)

Gronwald J, et al. ASCO 2009. Abstract 502.

 Neoadjuvant Study: Response to Treatment
Response No. %
Clinical response
CR 18 72
PR 7 28
Pathologic response
Complete pathologic 18 72
response
PR 7 28
No response 0 0
Residual disease in breast
None 19 76
< 1 cm 0 0
1-5 cm 6 24
> 5 cm 0 0
Number of lymph nodes positive
0 21 84
1-3 4 16
4-9 0 0
>9 0 0

Gronwald J, et al. ASCO 2009. Abstract 502.

 Cisplatino en BRCA1
Los tumores asociados a BRCA1 responden bien a quimioterapia
basadas en cisplatino

La elección de tratamiento puede optimizarse con evaluando el

BRCA1

Cisplatino
 Phase II Study With Olaparib: Rationale and
Design
• To assess the efficacy and tolerability of oral olaparib in BRCA1/BRCA2 mutation
carriers with breast cancer
• Multicenter proof-of-concept phase II study, single-arm sequential cohort design

Confirmed BRCA1 or BRCA2 mutation,

advanced refractory breast cancer
(stage IIIB/IIIC/IV) after failure of ≥ 1 previous
chemotherapies for advanced disease
Cohort 1 (enrolled first) Cohort 2*
Olaparib 400 mg PO BID (MTD) Olaparib 100 mg PO BID
28-day cycles 28-day cycles
(n = 27) (n = 27)

*Following an interim review of the emerging efficacy of each cohort, patients ongoing in 100-mg
BID cohort were permitted to crossover to receive the 400-mg BID dose.
MTD determined during phase I evaluation
Tutt A, et al. ASCO 2009. Abstract 501.
 Olaparib: Efficacy Results
ITT Cohort, n (%) Olaparib 400 mg BID Olaparib 100 mg BID
(n = 27) (n = 27)
ORR 11 (41)* 6 (22)*
CR 1 (4) 0
PR 10 (37) 6 (22)
*An additional 1 patient in the 400-mg cohort and 3 patients in the 100-mg cohort had unconfirmed responses.

Per Protocol Cohort, n (%) 400 mg BID 100 mg BID

(n = 26) (n = 24)
ORR 11 (42) 6 (25)†
CR 1 (4) 0
PR 10 (39) 6 (25)
†
An additional 3 patients in the 100-mg cohort had unconfirmed responses.

Tutt A, et al. ASCO 2009. Abstract 501.

 iPARP (Olaparib) en BRCA1/BRCA2
Primer reporte de terapia dirigida a los portadores de BRCA1/BRCA2
Olaparib como monoagente (400 mg BID) es muy activo en pacientes portadoras
de BRCA1/BRCA2 refractarias a varias líneas
ORR - ITT (RECIST): 41%
PFS (mediana): 5.7 meses
Buena tolerancia

Olaparib
“Proof-of-concept” de BRCA1/BRCA2 como diana
terapéutica en cáncer de mama y ovario
Tutt A, et al. ASCO 2009. Abstract 501.
Fong PC., Boss DS, Yap T, et al. Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers.
N Engl J Med 2009 361: 123-134
 Triple-Negative BC Shares Clinical and Pathologic
Features With BRCA1-Related BC
Characteristics Hereditary BRCA1 Triple Negative/Basal Like[1-3]
ER/PR/HER2 status Negative Negative
TP53 status Mutant Mutant
BRCA1 status Mutational inactivation* Diminished expression*
Gene-expression pattern Basal like Basal like
Tumor histology Poorly differentiated Poorly differentiated
(high grade) (high grade)
Chemosensitivity to Highly sensitive Highly sensitive
DNA-damaging agents

*BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID4. [4]

1. Perou C, et al. Nature. 2000;408:747-752. 2. Cleator S, et al. Lancet Oncology. 2007;8:235-244. 3. Sorlie T, et
al. Proc Natl Acad Sci U S A. 2001;98:10569-10674. 4. Miyoshi Y, et al. Int J Clin Oncol. 2008;13:395-400.
O’Shaughnessy J, et al. ASCO 2009. Abstract 3.
 Phase II Triple-Negative BC Study: Treatment
Schema

BSI-201: Metastatic TNBC

small molecule (N = 120)
PARP inhibitor
RANDOMIZE

Gem* 1000 mg/m2 IV on BSI-201 5.6 mg/kg IV on Days 1, 4, 8, 11 +

21-day Gem 1000 mg/m2 IV on Days 1, 8 +
Days 1, 8 +
Carbo AUC 2 IV on Days 1, 8
cycle Carbo AUC 2 IV on Days 1, 8

Restaging
every 2 Cycles
*Patients randomized to gem/carbo alone could crossover to receive gem/carbo +
BSI-201 at disease progression.
O’Shaughnessy J, et al. ASCO 2009. Abstract 3.
 BSI-201: Preliminary Efficacy Results*

Gem/Carbo BSI-201 + P Value

(n = 44) Gem/Carbo
(n = 42)
Objective response rate, n (%) 7 (16) 20 (48) .002
Clinical benefit rate,† n (%) 9 (21) 26 (62) .0002
Median PFS, mos 3.3 6.9 <.0001
Median OS, mos 5.7 9.2 .0005
*Includes patients enrolled before September 30, 2008, and patients who had a confirmed response or disease
progression.
†
Clinical benefit rate = CR + PR + SD ≥ 6 mos.

O’Shaughnessy J, et al. ASCO 2009. Abstract 3.

O’Shaughnessy J, et al. ASCO 2009. Abstract 3.
O’Shaughnessy J, et al. ASCO 2009. Abstract 3.
 Inhibición de la PARP-1 en Triple Negativos (y BRCA)

Se estableció sobre-expresión de PARP en la mayoría de los TNBC

BSI-201 + gem/carbo fue bien tolerado, sin incremento en las toxicidadas
asociadas a quimioterapia
BSI-201 mejoró los desenlaces clínicos relevantes
Clinical benefit rate (62% vs 21%; P = .0002)
ORR (48% vs 16%; P = .002)
Median PFS (6.9 vs 3.3 mos; P < .0001)
Median OS (9.2 vs 5.7 mos; P = .0005)
Estos resultados justifican la investigación del BS1-201 en estudios Fase III

iPARP1

O’Shaughnessy J, et al. ASCO 2009. Abstract 3.

 RIBBON-1
Addition of Bevacizumab to Standard Chemotherapy Regimens Improves
PFS in First-line Treatment of Patients With Metastatic Breast Cancer
Cáncer
Cáncermama
mamametastásico
metastásico Metodología
Metodología Desenlace
Desenlaceprincipal
principal
PFS:
PFS:Supervivencia
Supervivencialibre
librede
de
 Pacientes
Pacientescon
concáncer
cáncerde
demama
mama  Aleatorización
Aleatorización2:1
2:1 progresión
progresión
metastásico.
metastásico.  Estratificado
Estratificadopor
por
 Quimionaive
Quimionaive  Intervalo
Intervalolibre
librede
deenfermedad
enfermedad
 N=1273
N=1273  Terapia
Terapia adyuvanteprevia
adyuvante previa
 Número
Númerode desitios
sitiosmetastásicas
metastásicas
 Opciones
Opcionesde
deQT
QT  Selección
Selecciónde
deQT
QT
 Capecitabina
Capecitabina1000
1000mg/m2
mg/m2dos QT
veces
dos QT ++ Bev
Bev
veces por día x14 días, cada21
por día x14 días, cada 21
 Docetaxel
Docetaxel N= 824
 nabPaclitaxel
nabPaclitaxel
 Antraciclinas.
Antraciclinas.
Elección
Elección de
de QT
QT
Abreviaturas
Abreviaturas

 QT:
QT:Quimioterapia
Quimioterapia
Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized double-  Bev:
Bev:Bevacizumab
Bevacizumab1515mg/kg
mg/kg
blind, placebo-controlled, phase III trial of chemotherapy with or QT
QT ++ Placebo
Placebo cada 3 semanas.
cada 3 semanas.
without bevacizumab (B) for first-line treatment of HER2-negative  Placebo:
locally recurrent or metastatic breast cancer (MBC). Program and N= 413
Placebo:Placebo
PlaceboIV
IVcada
cada33
semanas
semanas
abstracts of the 2009 Annual Meeting of the American Society of
Clinical Oncology; May 29 - June 2, 2009; Orlando, Florida. Abstract
1005.
 RIBBON-1: Objective Response Rates

Cape T/Anthra CR
60 P = .0097 P = .0054 PR
51.3
50
37.9
Percentage

40 35.4
30 23.6
20
10
0
PL BV PL BV
Measurable
disease, n 161 325 177 345

Includes only patients with measurable disease at baseline

Robert N, et al. ASCO 2009. Abstract 1005.
 RIBBON-1
Addition of Bevacizumab to Standard Chemotherapy Regimens Improves
PFS in First-line Treatment of Patients With Metastatic Breast Cancer
Outcome Capecitabine
Bevacizumab Placebo HR  P
(n = 409) (n = 206) (95% CI) Value
Median PFS,
mos
•Investigator 8.6 5.7
0.69
.0002
assessed (0.56-0.84)
0.68
•IRC 9.8 6.2
0.54-0.86)
.0011

Median OS, 0.85

29.0 21.2 .27
mos (0.63-1.14)
1-yr survival,
% 81 74 .076
ORR,* % 35.4 23.6 .0097

Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized double-blind, placebo-controlled, phase III trial of chemotherapy
with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC).
Program and abstracts of the 2009 Annual Meeting of the American Society of Clinical Oncology; May 29 - June 2, 2009;
Orlando, Florida. Abstract 1005.
 RIBBON-1
Addition of Bevacizumab to Standard Chemotherapy Regimens Improves
PFS in First-line Treatment of Patients With Metastatic Breast Cancer
Outcome Taxane or Anthracycline
Bevacizumab Placebo HR PValue
(n = 415) (n = 207) (95% CI)
Median PFS,
mos
•Investigator 9.2 8.0
0.64
< .0001
assessed (0.52-0.80)
0.77
•IRC 10.7 8.3
(0.60-0.99)
.040

Median OS, 25.2 23.8 1.03 .83

mos (0.77-1.38)
1-yr survival, % 81 83 .44
ORR,* % 51.3 37.9 .0054

Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized double-blind, placebo-controlled, phase III trial of chemotherapy
with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC).
Program and abstracts of the 2009 Annual Meeting of the American Society of Clinical Oncology; May 29 - June 2, 2009;
Orlando, Florida. Abstract 1005.
 RIBBON-1
Addition of Bevacizumab to Standard Chemotherapy Regimens Improves
PFS in First-line Treatment of Patients With Metastatic Breast Cancer
Patient Subgroup, HR for Capecitabine Taxane or Anthracycline
PFS
All patients 0.67 0.66
Disease-free interval, mos
•≤ 12 mos 0.81 0.62
•> 12 mos 0.63 0.69
Number of metastatic sites
•< 3 0.63 0.65
•≥ 3 0.74 0.64
Previous adjuvant
chemotherapy
•Yes 0.64 0.67
•No 0.80 0.64

Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized double-blind, placebo-controlled, phase III trial of chemotherapy
with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC).
Program and abstracts of the 2009 Annual Meeting of the American Society of Clinical Oncology; May 29 - June 2, 2009;
Orlando, Florida. Abstract 1005.
 RIBBON-1: Overall Survival
Cape T/Anthra
PL BV PL BV
(n = 206) (n = 409) (n = 207) (n = 415)
% of deaths 35 30 35 34
Median OS, mos 21.2 29.0 23.8 25.2
HR (95% CI) 0.85 (0.63-1.14) 1.03 (0.77-1.38)
P value .27 .83
1-yr survival rate, % 74 81 83 81
P value .076 .44

Robert N, et al. ASCO 2009. Abstract 1005.

 Bevacizumab + Quimioterapia en Cáncer de Mama

 Estudio prospectivo, aleatorizado controlado

 Más eficaz que quimioterapia sin Bevacizumab.
 Corrobora el E2100, AvADO
 No incremento en la supervivencia global
 Se expanden las opciones:
 Bevacizumab + Capecitabina
 Bevacizumab + Antraciclinas
 Bevacizumab + Docetaxel o NabPaclitaxel

RIBBON-1

Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized double-blind, placebo-controlled, phase III trial of chemotherapy
with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC).
Program and abstracts of the 2009 Annual Meeting of the American Society of Clinical Oncology; May 29 - June 2, 2009;
Orlando, Florida. Abstract 1005.
 MIRROR Study: Schema
Selected from Netherlands
Cancer Registry
(N = 3205)  No pathology
review
 Macrometastases
 Unfavorable tumor
characteristics
 Other reasons
Inclusion after central
pathology review
(n = 2680)

SN only cALND axRT

(n = 1218) (n = 1314) (n = 148)

Present analysis: categorized by SN status

Tjan-Heijnen et al, ASCO 2009. Abstract 506. Reprinted with permission.
 Micrometastases and Isolated Tumor Cells: Relevant and Robust or
Rubbish? (MIRROR) study
Micrometástasis en ganglio centinela incrementa el riesgo de recurrencia axilar si
no se practica tratamiento dirigido a la axila
%
% de
de Recurrencia
Recurrencia axilar
axilar aa 55 años
años (1.7%)
(1.7%)

1.6% (n=125)
T
A xR
o MIRROR
MIRROR
LD
AN 2.3% (n=732)  Cohorte
Cohortede
de2680
2680pacientes
pacientesenen
Holanda con carcinoma de mama
Holanda con carcinoma de mama
Nada temprano
0.9% (n=450) tempranoaaquienes
quienesse
sele
lepracticó
practicó
N0 Ganglio Centinela Axilar
Ganglio Centinela Axilar
A xRT
Do  Tratadas
ANL Tratadasentre
entre1997-2005
1997-2005
N0i+  Retrospectivo
11 Retrospectivo//Cohorte
Cohorte
 ANLD:
ANLD:Disección
Disecciónganglonar
ganglonaraxilar
axilar
Nad
a 2.0% (n=345)  AxRT:
N1
m AxRT:Radioterapia
Radioterapiaaalalaaxila
axila
i
ANLD o
22 AxRT 1.0% (n=887)

Na
d a
5.1% (n=141)
33

Tjan-Heijnen VC, et al. J Clin Oncol 27:15s, 2009 (suppl; abstr CRA506). LemaTeachFiles® - 2009
 Gem/Docetaxel  Cap vs Cap/Docetaxel  Gem
Gem/Doc vs Cap/Doc hasta progresión, seguido por Capecitabina o
Gemcitabina, respectivamente
Cáncer
Cáncermama
mamametastásico
metastásico Metodología
Metodología Desenlace
Desenlaceprincipal
principal
 Pacientes
Pacientescon
concáncer
cáncerde
demama  Estratificado TTP:
TTP: Tiempo
Tiempoaalalaprogresión
progresión
mama Estratificadopor
por
metastásico o localmente
metastásico o localmente
avanzado.  Primera
Primeraoosegunda
segundalínea
línea
avanzado.
 Quimionaive,  Metástasis
Metástasisdedepredominio
predominio
Quimionaive,oonono
visceral
visceral
 N=475
N=475  Antraciclinas
Antraciclinasprevias
previas
 Desempeño ECOG
Desempeño ECOG
 Opciones
Opcionesde
deQT
QT Gem/Doc
 E.E.Medible
Medible//No
NoMedible
Medible Gem/Doc Capecitabina
Capecitabina
 Gem/Doc:
Gem/Doc:Gemcitabine
Gemcitabine10001000
mg/m2
mg/m2díadía11yy8;
8;Docetaxel
Docetaxel75 75 N= 239
mg/m2 día 1; cada 21 días.
mg/m2 día 1; cada 21 días.
 Cap/Doc:
Cap/Doc:Capecitabine
Capecitabine1000
1000
mg/m2
mg/m2 2 veces por día, día1-
2 veces por día, día 1-
14;
14;Docetaxel
Docetaxel75 75mg/m2
mg/m2día día1;
1; Aleatorizado
Aleatorizado
cada 21 días
cada 21 días
 Hasta
Hastaprogresión
progresión

Seidman AD, Brufsky A, Ansari RH, et al. Phase III trial of

Cap/Doc
Cap/Doc Gemcitabina
Gemcitabina
gemcitabine plus docetaxel (GD) compared to capecitabine plus
N= 236
docetaxel (CD) with planned crossover to the alternate single agent
in metastatic breast cancer (MBC). Program and abstracts of the
2009 Annual Meeting of the American Society of Clinical Oncology;
May 29 - June 2, 2009; Orlando, Florida. Abstract 1000.
 Gem/Docetaxel  Cap vs Cap/Docetaxel  Gem
Gem/Doc vs Cap/Doc hasta progresión, seguido por Capecitabina o
Gemcitabina, respectivamente

Median Time to Induction Phase Crossover Phase

Progressive
Disease, Mos  Gemcitabine/ Capecitabine/ Gemcitabine/ Capecitabine/
(95% CI) Docetaxel Docetaxel Docetaxel  Docetaxel 
(n = 239) (n = 236) →Capecitabine →Gemcitabine
(n = 76) (n = 80)

Individual 9.3 8.9 4.5 2.3

groups (7.7-10.8) (7.4-11.1) (2.1-7.8) (2.0-3.8)
P value .385 .145

Seidman AD, Brufsky A, Ansari RH, et al. Phase III trial of

gemcitabine plus docetaxel (GD) compared to capecitabine plus
docetaxel (CD) with planned crossover to the alternate single agent
in metastatic breast cancer (MBC). Program and abstracts of the
2009 Annual Meeting of the American Society of Clinical Oncology;
May 29 - June 2, 2009; Orlando, Florida. Abstract 1000.
 Trastuzumab-DM1 Active, Safe, and Well Tolerated in Patients With
Previously Treated HER2-Positive Metastatic Breast Cancer
-Estudio Fase II Desenlace
Desenlaceprincipal
principal--OR:
OR: Respuesta
Respuestaobjetiva
objetivapor
porRECIST
RECIST––por
por
evaluador independiente
evaluador independiente
Cáncer
Cáncermama
mamametastásico
metastásico Outcome Independent Review Investigator Assessment
(n = 112) (n = 112)
 HER2
HER2positiva
positiva
 Previamente
Previamentetratadas
tratadascon
con
Best objective response,
trastuzumab
trastuzumab
%
 >=
>=Líneas
Líneasde
deQT
QT •CR 0 2.7
 N=112
N=112 •PR 25.0 35.7
 Número
Númeromediano
medianode delíneas
líneasde
de •SD 48.2 38.4
quimioterapia: 3 (rango: 1-12)
quimioterapia: 3 (rango: 1-12) •PD 18.8 19.6
 Trastuzumab-DM1:
Trastuzumab-DM1:Combina
inhibición de HER2
Combina
por
•Unknown 8.0 3.6
inhibición de HER2 por
trastuzumab
trastuzumabconconelelagente
agente Overall response rate, 
% (95% CI) 25.0 (17.5-33.6) 38.4 (29.8-47.5)
antimicrotubular DM1
antimicrotubular DM1
 Trastuzumab-DM1
Trastuzumab-DM13.6 3.6mg/kg
mg/kg •Efficacy-evaluable
given by intravenous infusion
given by intravenous infusion confirmed HER2-positive 32.0 (22.1-43.0) 48.0 (36.3-59.9)
over
over30-60
30-60minutes
minutesevery
every33 disease (n = 75)
weeks
weeksuntil
untildisease
diseaseprogression
progression
Hasta progresión
Hasta progresión •Efficacy-evaluable
confirmed HER2-normal 4.8 (< 1-21.8)* 9.5 (1.7-29.8) †
disease (n = 21)
Vogel CL, Burris HA, Limentani S, et al. A
Clinical benefit rate,‡ %
phase II study of trastuzumab-DM1 (T-DM1), 34.8 (26.1-43.9) 44.6 (35.5-54.3)
(95% CI)
a HER2 antibody-drug conjugate, in patients
with HER2-positive metastatic breast cancer. •Efficacy-evaluable
Program and abstracts of the 2009 Annual confirmed HER2-positive 44.0 (33.2-55.5) 54.7 (43.0-66.2)
Meeting of the American Society of Clinical disease (n = 75)
Oncology; May 29 - June 2, 2009; Orlando,
Florida. Abstract 1017.
Median PFS, mos 4.9 4.9
 Trastuzumab-DM1 Active, Safe, and Well Tolerated in Patients With
Previously Treated HER2-Positive Metastatic Breast Cancer
-Estudio Fase II

Outcome in Patients Independent Review Investigator Assessment

Previously Treated with (n = 67) (n = 67)
Trastuzumab and
Lapatinib

ORR, % (95% CI) 23.9 (14.3-35.4) 35.8 (25.2-48.2)

Clinical benefit rate,* %
(95% CI) 35.8 (25.2-48.2) 44.8 (32.8-56.9)

Vogel CL, Burris HA, Limentani S, et al. A phase II study of trastuzumab-DM1 (T-DM1), a HER2 antibody-drug conjugate, in patients with
HER2-positive metastatic breast cancer. Program and abstracts of the 2009 Annual Meeting of the American Society of Clinical Oncology;
May 29 - June 2, 2009; Orlando, Florida. Abstract 1017.
Cáncer de mama Highlights ASCO 2009
Otros avances
„Individualización“ del Clarificación del significado N1mi
tratamiento basado en
biomarcadores Utilidad (validada prospectivamente) del
uPA / PAI en Cáncer de mama temprano

Avances tecnológicos

BRCA deficientes
iPARP1 activos en triple negativos
iPARP1 activos en mutBRCA Nuevas opciones
Cisplatino activo en mutBRCA Uso de Bevacizumab expandido
T-DM1 para pacientes HER2+
iRANKL (Denosumab) activo en enfermedad ósea
 Cáncer de GI no colorrectal
Cáncer
Cáncer de
de páncreas
páncreas
ESPAC-3(v2): Gemcitabina vs FU/LV adyuvante
CONKO-4: Enoxaparina en cáncer de páncreas

Cáncer
Cáncer biliar
biliar
Estudios ABC-02: Gemcitabina + Cisplatino en cáncer avanzado
seleccionados
como los más
importantes
Cáncer
Cáncer gástrico
gástrico
ToGA: Trastuzumab en Cáncer Gástrico HER2 positivo

5 Estudios (5 RCTs) Tumores

Tumores neuroendocrinos
neuroendocrinos
PROMID: Octreótido LAR en TN metastásicos
 ToGA Trial

Van Cutsem E, Kang Y, Chung H, et al. Efficacy results from the ToGA trial: a phase III study of trastuzumab added to standard
chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC). Program
and abstracts of the 2009 Annual Meeting of the American Society of Clinical Oncology; May 29 - June 2, 2009; Orlando, Florida.
Abstract LBA4509.
Van Cutsem E, Kang Y, Chung H, et al. Efficacy results from the ToGA trial: a phase III study of trastuzumab added to standard
chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC). Program
and abstracts of the 2009 Annual Meeting of the American Society of Clinical Oncology; May 29 - June 2, 2009; Orlando, Florida.
Abstract LBA4509.
 Trastuzumab en cáncer gástrico avanzado HER2+
Adenocarcinoma gástrico (o de la unión gastroesofágica) avanzado (CGA),
No curable.
Desempeño PS 0-2 CGA
CGA –– HER2+
HER2+
HER2+ (22.1% de los tamizados) PS 0-2
PS 0-2

ToGA
ToGA

n=584  TCF: Trastuzumab 8 mg/kg x1,

seguido por 6 mg/kg cada 3
semanas + CF
Trastuzumab
Trastuzumab  CF: CIsplatino 80 mg/m2 cada
n=294 290 CF
CF 3 semanas + Capecifabina:
CF
CF 1000 mg/m2 dos veces por día
14 días, cada 21 días (FU
infusional también aceptado)

 HR para PFS: 0.71,

p=0.0002
PFS:
PFS: 6.7
6.7 m
m OS:
OS: 13.8
13.8 m
m PFS:
PFS: 5.5
5.5 m
m OS:
OS: 11.1
11.1 m
m  HR para OS: 0.74,
p=0.0046

• Trastuzumab + Cisplatino + Fluoropirimidinas aumentan la tasa de respuesta,

supervivencia libre de progresión, y supervivencia global en pacientes con cáncer
gástrico avanzado HER2+.
LemaTeachFiles® - 2009
Van Cutsem E, et al. J Clin Oncol 27:18s, 2009 (suppl; abstr LBA4509)
 Gemcitabina + Cisplatino en cáncer biliar avanzado (ABC)
– UK – ABC 02
Adenocarcinoma biliar avanzado (Colangiocarcinoma, carcinoma de vesícula biliar, ampolla de Vater)
metastásico o recurrente
ABC
ABC
Desempeño PS 0-2 PS 0-2 PS 0-2

UK
UK –– ABC02
ABC02

n=410  Cisplatino + Gemcitabina:

Cisplatino 25 mg/m2 día 1 y 8;
Gemcitabina 1000 mg/m2 día
Cisplatino 1 y 8; cada 21 días. Hasta 8
Cisplatino Gemcitabina ciclos.
n=204 206 Gemcitabina
Gemcitabina
Gemcitabina  Gemcitabina: 1000 mg/m2 día
1, 8 y 15, cada 28 días. Hasta
por 6 ciclos

 HR para PFS: 0.72,

p=0.003
PFS:
PFS: 8.4
8.4 m
m OS:
OS: 11.7
11.7 m
m PFS:
PFS: 6.5
6.5 m
m OS:
OS: 8.3
8.3 m
m  HR para OS: 0.7,
p=0.002

• La combinación con Cisplatino + Gemcitabina incrementa la supervivencia de pacientes

con carcinoma avanzado de vía biliar, y se establece un nuevo estándar de tratamiento.

Valle JW, et al. J Clin Oncol 27:18s, 2009 (suppl; abstr 4503) LemaTeachFiles® - 2009
Neoptolemos J, Büchler M, Stocken DD. ESPAC-3(v2): A multicenter, international, open-label, randomized, controlled phase III
trial of adjuvant 5-fluorouracil/folinic acid (5-FU/FA) versus gemcitabine (GEM) in patients with resected pancreatic ductal
adenocarcinoma. J Clin Oncol 27:18s, 2009 (suppl; abstr LBA4505)
 ESPAC-3 v2

Neoptolemos J, Büchler M, Stocken DD. ESPAC-3(v2): A multicenter, international, open-label, randomized, controlled phase III
trial of adjuvant 5-fluorouracil/folinic acid (5-FU/FA) versus gemcitabine (GEM) in patients with resected pancreatic ductal
adenocarcinoma. J Clin Oncol 27:18s, 2009 (suppl; abstr LBA4505)
Riess H, Pelzer U, Deutschinoff G. A prospective, randomized trial of chemotherapy with or without the low molecular weight
heparin (LMWH) enoxaparin in patients (pts) with advanced pancreatic cancer (APC): Results of the CONKO 004 trial. J Clin
Oncol 27:18s, 2009 (suppl; abstr LBA4506)
Riess H, Pelzer U, Deutschinoff G. A prospective, randomized trial of chemotherapy with or without the low molecular weight
heparin (LMWH) enoxaparin in patients (pts) with advanced pancreatic cancer (APC): Results of the CONKO 004 trial. J Clin
Oncol 27:18s, 2009 (suppl; abstr LBA4506)
Riess H, Pelzer U, Deutschinoff G. A prospective, randomized trial of chemotherapy with or without the low molecular weight
heparin (LMWH) enoxaparin in patients (pts) with advanced pancreatic cancer (APC): Results of the CONKO 004 trial. J Clin
Oncol 27:18s, 2009 (suppl; abstr LBA4506)
Riess H, Pelzer U, Deutschinoff G. A prospective, randomized trial of chemotherapy with or without the low molecular weight
heparin (LMWH) enoxaparin in patients (pts) with advanced pancreatic cancer (APC): Results of the CONKO 004 trial. J Clin
Oncol 27:18s, 2009 (suppl; abstr LBA4506)
Riess H, Pelzer U, Deutschinoff G. A prospective, randomized trial of chemotherapy with or without the low molecular weight
heparin (LMWH) enoxaparin in patients (pts) with advanced pancreatic cancer (APC): Results of the CONKO 004 trial. J Clin
Oncol 27:18s, 2009 (suppl; abstr LBA4506)
Riess H, Pelzer U, Deutschinoff G. A prospective, randomized trial of chemotherapy with or without the low molecular weight
heparin (LMWH) enoxaparin in patients (pts) with advanced pancreatic cancer (APC): Results of the CONKO 004 trial. J Clin
Oncol 27:18s, 2009 (suppl; abstr LBA4506)
Riess H, Pelzer U, Deutschinoff G. A prospective, randomized trial of chemotherapy with or without the low molecular weight
heparin (LMWH) enoxaparin in patients (pts) with advanced pancreatic cancer (APC): Results of the CONKO 004 trial. J Clin
Oncol 27:18s, 2009 (suppl; abstr LBA4506)
 PROMID: Phase IIIb Octreotide LAR in
Metastatic Neuroendocrine Tumors

Pts with newly Placebo

diagnosed, (n = 43)
Treatment
treatment-naive continued until
neuroendocrine progression
midgut tumors Octreotide LAR 30 mg IM
(N = 85) every 4 weeks
(n = 42)

Arnold R, Müller H, Schade-Brittinger, C et al. Placebo-controlled, double-blind, prospective, randomized study of

the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut
tumors: A report from the PROMID study group. Program and abstracts of the 2009 Annual Meeting of the
American Society of Clinical Oncology; May 29 - June 2, 2009; Orlando, Florida. Abstract 4508.
 PROMID: Octreotide LAR in Metastatic
Neuroendocrine Tumors—TTP, OS
• Primary endpoint: TTP
• Interim analysis of 85 pts
– 50% male – Hepatic tumor load: 0% to 10% in 60% of pts
– Median age: 63 years – CgA elevated in 66% of pts
• TTP significantly prolonged with octreotide LAR treatment in pts with lower hepatic
tumor load

Median TTP, Mos Pts, n Octreotide LAR Placebo P Value

All pts 85 14.3 6.0 .00007
Hepatic tumor load ≤ 10% 64 27.14 7.21 < .0001
Hepatic tumor load ≥ 10% 21 10.35 5.45 .345

• Median OS not yet reached for octreotide LAR (> 77.4 mos) vs placebo
(73.7 mos)
Arnold R, Müller H, Schade-Brittinger, C et al. Placebo-controlled, double-blind, prospective, randomized study of
the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut
tumors: A report from the PROMID study group. Program and abstracts of the 2009 Annual Meeting of the
American Society of Clinical Oncology; May 29 - June 2, 2009; Orlando, Florida. Abstract 4508.
 PROMID: Octreotide LAR in Metastatic
Neuroendocrine Tumors—Response

Octreotide LAR Placebo

Response, n
(n = 42) (n = 43)
CR 0 0
PR 1 1
SD 28 16
PD 10 23
Unknown 3 3

• Serious adverse events

– Gastrointestinal (octreotide LAR: n = 6; placebo: n = 8)
– Hematopoietic system (octreotide LAR: n = 5; placebo: n = 1)
Arnold R, Müller H, Schade-Brittinger, C et al. Placebo-controlled, double-blind, prospective, randomized study of
the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut
tumors: A report from the PROMID study group. Program and abstracts of the 2009 Annual Meeting of the
American Society of Clinical Oncology; May 29 - June 2, 2009; Orlando, Florida. Abstract 4508.
 PROMID: Phase IIIb Octreotide LAR in Metastatic
Neuroendocrine Tumors

Arnold R, Müller H, Schade-Brittinger, C et al. Placebo-controlled, double-blind, prospective, randomized study of

the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut
tumors: A report from the PROMID study group. Program and abstracts of the 2009 Annual Meeting of the
American Society of Clinical Oncology; May 29 - June 2, 2009; Orlando, Florida. Abstract 4508.
 PROMID: Phase IIIb Octreotide LAR in Metastatic
Neuroendocrine Tumors

Arnold R, Müller H, Schade-Brittinger, C et al. Placebo-controlled, double-blind, prospective, randomized study of

the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut
tumors: A report from the PROMID study group. Program and abstracts of the 2009 Annual Meeting of the American
Society of Clinical Oncology; May 29 - June 2, 2009; Orlando, Florida. Abstract 4508.
GI No Colorrectal Highlights ASCO 2009
Avances menores, pero reales Otros avances
LMWH (Enoxaparina) disminuye
riesgos de trombosis – sin impacto en
otras variables
Octreótido LAR es eficaz en T.
Neuroendocrinos

Cáncer gástrico
Anti HER2 (Trastuzumab) nuevo
estándar en Cáncer Gástrico HER2
positivo
Cáncer biliar
Gemcitabina + Cisplatino un nuevo
estándar en cáncer biliar avanzado
Cáncer de colon, recto y ano
Biomarcadores
Biomarcadores
QUASAR multigene RT-PCR assay
Biomarcadores del PETACC-3
CALGB 9581 LOH 18q
EREG / KRAS y respuesta a cetuximab

Terapia
Terapia adyuvante
adyuvante
Estudios Bevacizumab adyuvante: NSABP C08
seleccionados ACCENT Dbase: DFS a 2 años es un desenlace apropiado
como los más
importantes Oxaliplatino
Oxaliplatino
Star 01: Oxaliplatino neoadyuvante en recto
ACCORD-12: Oxaliplatino neoadyuvante en recto
Calcio y magnesio previene neurotoxicidad
Picoplatino es una alternativa al oxaliplatino

11 Estudios Cáncer
Cáncer de
de ano
ano
ACT II: QRT con Cisplatino es tan eficaz como mitomicina
James R, Wan S, Glynne-Jones R. A randomized trial of chemoradiation using mitomycin or cisplatin, with or without
maintenance cisplatin/5FU in squamous cell carcinoma of the anus (ACT II). J Clin Oncol 27:18s, 2009 (suppl; abstr LBA4009))
James R, Wan S, Glynne-Jones R. A randomized trial of chemoradiation using mitomycin or cisplatin, with or without
maintenance cisplatin/5FU in squamous cell carcinoma of the anus (ACT II). J Clin Oncol 27:18s, 2009 (suppl; abstr LBA4009))
James R, Wan S, Glynne-Jones R. A randomized trial of chemoradiation using mitomycin or cisplatin, with or without
maintenance cisplatin/5FU in squamous cell carcinoma of the anus (ACT II). J Clin Oncol 27:18s, 2009 (suppl; abstr LBA4009))
James R, Wan S, Glynne-Jones R. A randomized trial of chemoradiation using mitomycin or cisplatin, with or without
maintenance cisplatin/5FU in squamous cell carcinoma of the anus (ACT II). J Clin Oncol 27:18s, 2009 (suppl; abstr LBA4009))
 NSABP Protocol C-08: mFOLFOX ±
Bevacizumab in Stage II/III CRC

Arm A: mFOLFOX6 Q2W x 26

Pts with stage II or III (n = 1356)
colon adenocarcinoma
with ECOG PS of 0/11
(N = 2710) Arm B: mFOLFOX6 +
Bevacizumab 5 mg/kg Q2W x 26
(n = 1354)

 Pts stratified by number of positive lymph nodes and randomized between Days 29
and 50 postoperatively
 mFOLFOX6 regimen: LV 400 mg/m2 IV, 5-FU 400 mg/m2 IV, 5-FU 2400 mg/m2 over 46
hours; oxaliplatin 85 mg/m2 IV
 Primary endpoint: DFS

Wolmark N, et al. ASCO 2009. Abstract LBA4.

 NSABP Protocol C-08: 3-Yr DFS Results

100

80

60
DFS (%)

40
Events 3-Yr DFS
20 mFF6 + B 291 77.4 HR: 0.89 (P = .15)
mFF6 312 75.5
0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Yrs
Wolmark N, et al. ASCO 2009. Abstract LBA4.
 Highlights ASCO 2009
Cáncer Colon / Recto / Ano Otros avances
El año de los estudios Supervivencia libre de enfermedad a 2 años importante
NEGATIVOS o IRRELEVANTES Picoplatino o Calcio / Magnesio y neurotoxicidad
Mitomicina reemplazable por Cisplatino en Ano

Bevacizumab adyuvante
Muerto / Moribundo

Oxaliplatino neoadyuvante (Recto)

Incremento en toxicidad, sin beneficio adicional
 Melanomas
Biomarcadores
Biomarcadores en
en melanoma
melanoma
Ulceración tumoral y respuesta a interferón

Vacuna
Vacuna ++ HD
HD IL-2
IL-2 en
en Melanoma
Melanoma
Estudios gp100:209-217(210M)
seleccionados
como los más
importantes
Radioterapia
Radioterapia aa ganglios
ganglios linfáticos
linfáticos
Radioterapia adyuvante a campo comprometido

4 Estudios (2 RCTs)
RCTs) Terapia
Terapia dirigida
dirigida en
en Melanoma
Melanoma
1 Blockbuster
Blockbuster in
in the
the making
making Anti BRAF V600E: PLX4032
Anti cKit en Melanoma Acral
Eggermont et al. Abstract # 9007
Vacuna + IL-2 en Melanoma
Schwartzentruber DJ, Lawson D, Richards J, et al. A phase III multi-institutional randomized study of
immunization with the gp100:209-217(210M) peptide followed by high-dose IL-2 compared with
high-dose IL-2 alone in patients with metastatic melanoma. J Clin Oncol 27:18s, 2009 (suppl; abstr
CRA9011)
Schwartzentruber DJ, Lawson D, Richards J, et al. A phase III multi-institutional randomized study of
immunization with the gp100:209-217(210M) peptide followed by high-dose IL-2 compared with
high-dose IL-2 alone in patients with metastatic melanoma. J Clin Oncol 27:18s, 2009 (suppl; abstr
CRA9011)
Radioterapia Ganglios Linfáticos
Afectados en Melanoma
Henderson MA, Burmeister B, Thompson JF. Adjuvant radiotherapy and regional
lymph node field control in melanoma patients after lymphadenectomy: Results of
an intergroup randomized trial (ANZMTG 01.02/TROG 02.01). J Clin Oncol 27:18s,
2009 (suppl; abstr LBA9084)
Henderson MA, Burmeister B, Thompson JF. Adjuvant radiotherapy and regional
lymph node field control in melanoma patients after lymphadenectomy: Results of
an intergroup randomized trial (ANZMTG 01.02/TROG 02.01). J Clin Oncol 27:18s,
2009 (suppl; abstr LBA9084)
Terapia dirigida contra el BRAF en
Melanoma
Flaherty et al. Abstract # 9000
Flaherty et al. Abstract # 9000
Flaherty et al. Abstract # 9000
Flaherty et al. Abstract # 9000
Melanoma Highlights ASCO 2009
Otros avances
El „Tema“ en melanoma es Ulceración puede ser predictiva
caracterizar la biología y IL-2 todavía puede tener un nicho
aplicarla para el diseño de RT a ganglios potencialmente útil
terapias

Biología
Mutaciones de BRAF importantes
Mutación del c-Kit importante En el horizonte
Anti BRAF V600E: PLX4032
Anti c-Kit: Imatinib en subgrupos
 Sarcomas
Tumores
Tumores de
de Células
Células Gigantes
Gigantes del
del Hueso
Hueso
Denosumab

Tumores
Tumores Desmoides
Desmoides
Estudios Mutaciones de Beta Catenina son pronósticos
seleccionados
como los más
importantes
ASPS
ASPS
Cediranib es activo en Sarcomas de Tejidos Blandos
Alveolar

5 Estudios (1 RCT) GIST

GIST
Stop-and-go imatinib
IGFr en GIST
 RANKL Inhibition: Mechanism of Action

RANKL
RANK
Osteoclast Prefusion Denosumab
precursor osteoclast

Hormones Osteoclast
growth factors formation
Cytokines inhibited
Osteoclast
Apoptotic function and
osteoclast survival
Osteoblasts inhibited

Bone Formation

Inhibited Bone Resorption

Smith MR, et al. ASCO 2009. Abstract 9520

Denosumab – GCT of the bone

J Clin Oncol 27:15s, 2009 (suppl; abstr 10510)

J Clin Oncol 27:15s, 2009 (suppl; abstr 10510)
J Clin Oncol 27:15s, 2009 (suppl; abstr 10510)
J Clin Oncol 27:15s, 2009 (suppl; abstr 10523)
J Clin Oncol 27:15s, 2009 (suppl; abstr 10523)
J Clin Oncol 27:15s, 2009 (suppl; abstr 10523)
 Cediranib
• AZD2171
• Pan VEGFR, PDGFRa, PDGFRb TKI
• Oral
• Median half-life: 12-35 hours
• Dose: 45 mg QD
J Clin Oncol 27:15s, 2009 (suppl; abstr 10523)
J Clin Oncol 27:15s, 2009 (suppl; abstr 10523)
 Terapia dirigida a tumores mesenquimales
 Denosumab (RANKL antagonista) – eficaz en GCT
 Cediranib (Anti angiogénico) – eficaz en ASPS
 Suficiente para aprobación por FDA / EMEA ?
 Sólo proof-of-principle?

J Clin Oncol 27:15s, 2009 (suppl; abstr 10508)

J Clin Oncol 27:15s, 2009 (suppl; abstr 10501)
J Clin Oncol 27:15s, 2009 (suppl; abstr 10501)
J Clin Oncol 27:15s, 2009 (suppl; abstr 10501)
J Clin Oncol 27:15s, 2009 (suppl; abstr 10501)
GIST
J Clin Oncol 27:15s, 2009 (suppl; abstr 10508)
J Clin Oncol 27:15s, 2009 (suppl; abstr 10508)
J Clin Oncol 27:15s, 2009 (suppl; abstr 10508)
 Stop & Go Imatinib en GIST
 El imatinib no cura GIST metastásico
 Al suspender imatinib se acelera la progresión tumoral
 La supervivencia libre de evento luego de re-exposición es satisfactoria

GIST

J Clin Oncol 27:15s, 2009 (suppl; abstr 10508)

J Clin Oncol 27:15s, 2009 (suppl; abstr 10506)
J Clin Oncol 27:15s, 2009 (suppl; abstr 10506)
J Clin Oncol 27:15s, 2009 (suppl; abstr 10506)
 GIST con c-Kit / PDGFR nativos
Otra Enfermedad?
 Pobre respuesta al Imatinib
 Sobre-expresión del IGF1R
 Potenciales implicaciones terapéuticas

GIST

J Clin Oncol 27:15s, 2009 (suppl; abstr 10506)

Sarcomas Highlights ASCO 2009
Terapias dirigidas
El „Tema“ en sarcomas es iRANKL (Denosumab) en GCT
caracterizar la biología y Antiangiogénicos (Cediranib) en ASPS
aplicarla para el diseño de
terapias

Biología
Beta catenina implicada en
tumores desmoides Refinación
Suspender transitoriamente
IGF1R implicado en subgrupo de el imatinib en GIST puede
GIST ser una opción para un
subgrupo de pacientes
 Conclusiones
ASCO 2009 – en cáncer de mama, gastrointestinal, melanoma y
sarcomas
Ideas
Ideas para
para considerar
considerar mañana…
mañana… Ideas
Ideas nuevas
nuevas que
que prometen…
prometen…
 Gemcitabina
Gemcitabina ++ Cisplatino
Cisplatino en
en  Letalidad
Letalidad sintética
sintética
cánceres
cánceres biliares
biliares  iPARPs
iPARPs en
en tumores
tumores con
con deficiencia
deficiencia
 Trastuzumab
Trastuzumab ++ QT QT enen cáncer
cáncer del
del BRCA
BRCA
gástrico
gástrico Her2
Her2 positivo
positivo  Inhibidores
Inhibidores del
del BRAF
BRAF en
en melanoma
melanoma
 Disección
Disección ganglionar
ganglionar axilar
axilar en
en N1mi
N1mi
del
del ganglio
ganglio centinela
centinela
 Cisplatino
Cisplatino reemplaza
reemplaza aa mitomicina
mitomicina
en
en ano
ano
 Fluoruracilo
Fluoruracilo adyuvante
adyuvante en en páncreas
páncreas
 Anticoagulación
Anticoagulación profiláctica
profiláctica en
en
páncreas
páncreas avanzado
avanzado
 No
No transladar
transladar los
los resultados
resultados dede
metastásico
metastásico aa adyuvancia…
adyuvancia…