Asco 2009 - Highlights I - Lema - Mama - Gastrointestinal - Melanoma - Sarcoma

ASCO 2009 - Highlights

vidualizando 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 ños avanzando con la evidencia , y unos

s retrocediendo con el deseo ...

Manejo Loco-Regional

Radioterapia post mastectomía en enfermedad N1 Disección ganglionar axilar en micrometástasis

Biomarcadores en cáncer temprano

Estudios seleccionado s como los más importantes

Chemo-N0: uPA/PAI-1 70-gene profile I-SPY-Trial E2197: Perfil genético en triple negativos

Tratamiento sistémico enfermedad temprana Cisplatino en mutaciones BRCA Inhibidores de la CYP2D6 y tamoxifén Disfunción cognitiva con Letrozol / Tamoxifén Salud ósea e inhibición del RANKL

16 16 Estudios

Cáncer de mama 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

BRCA1 mutation carriers, primary breast cancer

Cisplatin 75 mg / m 2 q 3 wks IV x 4 cycles N = 10

25

S U R G E R Y

AC

§Primary endpoint: pCR (in breast and axilla, DCIS permitted)

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

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

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 (%) ORR CR PR

Olaparib 400 mg BID (n 27) 11 =(41)* 1 (4) 10 (37)

Olaparib 100 mg BID (n = 27) 6 (22)* 0 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 (%) ORR CR PR

†An

400 mg BID 11 (n =(42) 26) 1 (4) 10 (39)

100 mg BID 6 (25)† (n 0 = 24) 6 (25)

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 (high grade) Chemosensitivity to DNA- Highly sensitive damaging agents

Poorly differentiated (high grade) Highly sensitive

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

1 . Pe ro u C , e t a l. N a tu re . 2 0 0 0 ; 4 0 8 : 7 4 7 -7 5 2 . 2 . C le a to r S , e t a l. La n ce t O n co lo g y. 2 0 0 7 ; 8 : 2 3 5 -2 4 4 . 3 . S o rlie T , e t a l. Pro c N a tlA ca d S ciU S A . 2 0 0 1 ; 9 8 : 1 0 5 6 9 -1 0 6 7 4 . 4 . M iyo sh i Y , e t a l. In t J C lin O n co l. 2 0 0 8 ; 1 3 : 3 9 5 -4 0 0 .

O ’ S h a u g h n e ssy J, e t a l. A S C O 2 0 0 9 . A b stra ct 3 .

Phase II Triple-Negative BC Study: Treatment Schema BSI-201: small molecule PARP inhibitor

Metastatic TNBC (N = 120) RANDOMIZE

BSI-201 5.6 mg/kg IV on Days 1, 4, 8, 11 + Gem 1000 mg/m2 IV on Days 1, 8 + Carbo AUC 2 IV on Days 1, 8

Gem* 1000 mg/m2 IV on Days 1, 8 + Carbo AUC 2 IV on Days 1, 8

21-day cycle

Restaging every 2 Cycles *Patients randomized to gem/carbo alone could crossover to receive gem/carbo + BSI-201 at disease progression.

O ’ S h a u g h n e ssy J, e t a l. A S C O 2 0 0 9 . A b stra ct 3 .

BSI-201: Preliminary Efficacy Results* Objective response rate, n (%)

Gem/Carbo BSI-201 + Gem/Carbo P Value (n = 44) (n = 42) 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 ’ S h a u g h n e ssy J, e t a l. A S C O 2 0 0 9 . A b stra ct 3 .

O ’ S h a u g h n e ssy J, e t a l. A S C O 2 0 0 9 . A b stra ct 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 mama metastásico

§Pacientes con cáncer de mama metastásico. §Quimionaive §N=1273 §

§Opciones de QT

§Capecitabina 1000 mg/m2 dos veces por día x14 días, cada 21 §Docetaxel §nabPaclitaxel §Antraciclinas. §

Metodología

Desenlace principal PFS : Supervivencia libre de progresión

§Aleatorización 2:1

§Estratificado por

§Intervalo libre de enfermedad §Terapia adyuvante previa §Número de sitios metastásicas §Selección de QT §

QT + Bev N= 824

§

Elección de QT

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 firstline 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 .

Abreviaturas

QT + Placebo N= 413

§QT: Quimioterapia §Bev: Bevacizumab 15 mg/kg cada 3 semanas. §Placebo: Placebo IV cada 3 semanas

RIBBON-1: Objective Response Rates 60

Cape P = .0097

T/Anthra P = .0054

Percentage

50 40 30

35.4

CR PR

51.3

37.9

23.6

20 10 0

Measurable disease 161 , n

PL 325

BV

PL

BV

177

Includes only patients with measurable disease at baseline R o b e rt N , e t a l. A S C O 2 0 0 9 . A b stra ct 1005.

345

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 (n = 409) (n = 206)

Median PFS, mos Investigator 8.6 assessed IRC 9.8 Median OS, 29.0 mos 1-yr survival, 81 % ORR,* % 35.4

5.7 6.2 21.2

HR (95% CI)

P Value

0.69 (0.56-0.84) 0.68 0.54-0.86) 0.85 (0.63-1.14)

.0002 .0011 .27

74

.076

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

Median PFS, mos Investigator assessed IRC

Taxane or Anthracycline Bevacizumab Placebo (n = 415) (n = 207)

9.2

8.0

10.7

8.3

HR (95% CI)

PValue

0.64 (0.52-0.80) 0.77 (0.60-0.99) 1.03 (0.77-1.38)

< .0001 .040

Median OS, 25.2 mos 1-yr survival, % 81

23.8 83

.44

ORR,* %

37.9

.0054

51.3

.83

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 PFS

Capecitabine

Taxane or Anthracycline

All patients Disease-free interval, mos

0.67

0.66

≤ 12 mos > 12 mos Number of metastatic sites

0.81 0.63

0.62 0.69

<3 ≥ 3 Previous adjuvant chemotherapy Yes No

0.63 0.74

0.65 0.64

0.64 0.80

0.67 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 % value Median HR 1-yr P of(95% survival deaths OS, CI)mos rate, %

.076 (0.63-1.14) Cape PL 35 21.2 0.85 .27 74 BV 30 29.0 81 (n = 206) (n = 409)

R o b e rt N , e t a l. A S C O 2 0 0 9 . A b stra ct 1005.

.44 (0.77-1.38) T/Anthra PL 35 23.8 1.03 .83 83 8125.2 BV 34 (n = 207) (n = 415)

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 (n = 1218)

cALND (n = 1314)

Present analysis: categorized by SN status

T ja n -H e ijn e n e t a l, A S C O 2 0 0 9 . A b stra ct 5 0 6 . R e p rin te d w ith p e rm issio n .

axRT (n = 148)

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 Recurrencia axilar a 5 años ( 1 . 7 %)

1.6% (n=125) LD AN

o

RT Ax

MIRROR 2.3% (n=732)

Nada

N0

1

xR o A D ANL

N0i+

T

Nad a

N1 mi

2

ANLD o AxRT

Na da

0.9% (n=450)

§Cohorte de 2680 pacientes en Holanda con carcinoma de mama temprano a quienes se le practicó Ganglio Centinela Axilar §Tratadas entre 1997-2005 §Retrospectivo / Cohorte §ANLD: Disección ganglonar axilar §AxRT: Radioterapia a la axila

2.0% (n=345) 1.0% (n=887) 5.1% 3 ( n = 141 )

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 mama metastásico §Pacientes con cáncer de mama metastásico o localmente avanzado. §Quimionaive, o no §N=475 §

§Opciones de QT

§Gem / Doc: Gemcitabine 1000 mg/m2 día 1 y 8; Docetaxel 75 mg/m2 día 1; cada 21 días. §Cap / Doc: Capecitabine 1000 mg/m2 2 veces por día, día 1-14; Docetaxel 75 mg/m2 día 1; cada 21 días §Hasta progresión § §

Metodología

Desenlace principal TTP : Tiempo a la progresión

§Estratificado por

§Primera o segunda línea §Metástasis de predominio visceral §Antraciclinas previas §Desempeño ECOG §E. Medible / No Medible §

Gem/Doc

Capecitabi na

N= 239

Aleatoriza do

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 .

Cap/Doc N= 236

Gemcitabin a

Gem / Docetaxel  Cap vs Cap / Docetaxel  Gem Gem/Doc vs Cap/Doc hasta progresión, seguido por Capecitabina o Gemcitabina, respectivamente

P value Median Individual .385 Induction Gemcitabine 9.3 Phase Capecitabin .145 8.9 Crossover Phase Gemcitabine 4.5 Capecitabin 2.3 Time to groups / Docetaxel (7.4-11.1) (7.7-10.8) e/ Docetaxel (2.1-7.8) / e/ (2.0-3.8) Progressive (n = 239) (n = 236) Docetaxel Docetaxel Disease, →Capecitab →Gemcitabi Mos ine ne (95% CI) (n = 76) (n = 80)

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 Cáncer mama metastásico

§HER2 positiva §Previamente tratadas con trastuzumab §>= Líneas de QT §N = 112 §Número mediano de líneas de quimioterapia: 3 (rango: 112) §Trastuzumab - DM1: Combina inhibición de HER2 por trastuzumab con el agente antimicrotubular DM1 §Trastuzumab - DM1 3.6 mg/kg given by intravenous infusion over 30-60 minutes every 3 weeks until disease progression Hasta progresión § §

Vogel CL, Burris HA, Limentani S, et al. A phase II study of trastuzumabDM1 (T-DM1), a HER2 antibody-drug conjugate, in patients with HER2positive 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 .

Desenlace principal - OR : Respuesta objetiva por RECIST – por evaluador independiente

Outcome

Independent Review (n = 112)

Best objective response, % CR 0 PR 25.0 SD 48.2 PD 18.8 Unknown 8.0 Overall response rate, 25.0 (17.5-33.6) % (95% CI) Efficacy-evaluable 32.0 (22.1-43.0) confirmed HER2positive disease (n = 75) Efficacy-evaluable 4.8 (< 1-21.8)* confirmed HER2-normal disease (n = 21) Clinical benefit rate,‡ % 34.8 (26.1-43.9) (95% CI) Efficacy-evaluable 44.0 (33.2-55.5) confirmed HER2positive disease (n = 75) Median PFS, mos 4.9

Investigator Assessment (n = 112) 2.7 35.7 38.4 19.6 3.6 38.4 (29.8-47.5) 48.0 (36.3-59.9) 9.5 (1.7-29.8) † 44.6 (35.5-54.3) 54.7 (43.0-66.2) 4.9

Trastuzumab - DM1 Active , Safe , and Well Tolerated in Patients With Previously Treated HER2 Positive Metastatic Breast Cancer

-Estudio Fase II

Clinical Outcome ORR, % benefit (95% in CI) 35.8 Independent 23.9 (14.3-35.4) (25.2-48.2) Patients rate,* % (95% Previously CI) Review Treated with (n = 67) Trastuzumab and Lapatinib

44.8 (32.8-56.9) Investigator 35.8 (25.2-48.2) Assessment (n = 67)

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 .

Highlights ASCO 2009

Cáncer de mama

„Individualización“ del tratamiento basado en biomarcadores Avances tecnológicos

Otros avances

Clarificación del significado N1mi Utilidad (validada prospectivamente) del uPA / PAI en Cáncer de mama temprano

BRCA deficientes iPARP1 activos en triple negativos iPARP1 activos en mutBRCA Cisplatino activo en mutBRCA

Nuevas opciones Uso de Bevacizumab expandido T-DM1 para pacientes HER2+ iRANKL (Denosumab) activo en enfermedad ósea

Cáncer de GI no colorrectal Cáncer de páncreas ESPAC-3(v2): Gemcitabina vs FU/LV adyuvante CONKO-4: Enoxaparina en cáncer de páncreas

Cáncer biliar

Estudios seleccionado s como los más importantes

ABC-02: Gemcitabina + Cisplatino en cáncer avanzado

Cáncer gástrico ToGA: Trastuzumab en Cáncer Gástrico HER2 positivo

55 Estudios Estudios (5 (5 RCTs) RCTs)

Tumores 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 – HER2+ HER2+ (22.1% de los tamizados) PS 0-2

ToGA n=584

n=294

Trastuzumab CF

PFS: 6.7 m

OS: 13.8 m

290

PFS: 5.5 m

CF

§TCF: Trastuzumab 8 mg/kg x1, seguido por 6 mg/kg cada 3 semanas + CF §CF: CIsplatino 80 mg/m2 cada 3 semanas + Capecifabina: 1000 mg/m2 dos veces por día 14 días, cada 21 días (FU infusional también aceptado)

OS: 11.1 m

§HR para PFS: 0.71, p=0.0002 §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+. Van Cutsem E , et al. J Clin Oncol  27:18s, 2009 (suppl; abstr LBA4509)

LemaTeachFiles® - 2009

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 Desempeño PS 0-2 PS 0-2

UK – ABC02 n=410

n=204

Cisplatino Gemcitabina

PFS: 8.4 m

OS: 11.7 m

206

Gemcitabin a

PFS: 6.5 m

§Cisplatino + Gemcitabina: Cisplatino 25 mg/m2 día 1 y 8; Gemcitabina 1000 mg/m2 día 1 y 8; cada 21 días. Hasta 8 ciclos. §Gemcitabina: 1000 mg/m2 día 1, 8 y 15, cada 28 días. Hasta por 6 ciclos §

OS: 8.3 m

§HR para PFS: 0.72, p=0.003 §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 diagnosed, treatment-naive neuroendocrine midgut tumors (N = 85)

Placebo (n = 43)

Octreotide LAR 30 mg IM every 4 weeks (n = 42)

Treatment continued until progression

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



Median age: 63 years



Hepatic tumor load: 0% to 10% in 60% of pts

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

21

10.35

5.45

.345





Hepatic tumor load ≥ 10% 

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 Response, n CR PR SD PD Unknown



3 Octreotide 0 1 28 10 LAR (n = 42)

3 Placebo 0 1 16 23 (n = 43)

Serious adverse events

Gastrointestinal (octreotide LAR: n = 6; placebo: n = 8) Arnold R,  Müller H, Schade-Brittingersystem , C et al. Placebo - controlled , double blind Hematopoietic (octreotide LAR: n -= 5;, prospective , randomized study of the effect of octreotide LAR in the control of tumor growth placebo: in patients n with metastatic neuroendocrine midgut tumors : A report = 1) 

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 .

Highlights ASCO 2009

I No Colorrectal

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 bilia Gemcitabina + Cisplatino un nuevo estándar en cáncer biliar avanzado

Cáncer de colon, recto y ano Biomarcadores QUASAR multigene RT-PCR assay Biomarcadores del PETACC-3 CALGB 9581 LOH 18q EREG / KRAS y respuesta a cetuximab

Terapia adyuvante

Estudios seleccionado s como los más importantes

Bevacizumab adyuvante: NSABP C08 ACCENT Dbase: DFS a 2 años es un desenlace apropiado

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 11 Estudios

Cáncer de 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 Pts with stage II or III colon adenocarcinoma with ECOG PS of 0/11 (N = 2710)

Arm A: mFOLFOX6 Q2W x 26 (n = 1356)

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

DFS (%)

80 60 40 mFF6 + B mFF6

20 0

0

0.5

Events 3-Yr DFS 291 77.4 312 75.5 1 .0

1.5

2.0 Yrs

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

HR: 0.89 (P = .15)

2.5

3.0

3.5

Highlights ASCO 2009 ncer Colon / Recto / Ano

Otros avances

El año de los estudios NEGATIVOS o IRRELEVANTES

Supervivencia libre de enfermedad a 2 años importante Picoplatino o Calcio / Magnesio y neurotoxicidad Mitomicina reemplazable por Cisplatino en Ano

Bevacizumab adyuvante Muerto / Moribundo

Oxaliplatino neoadyuvante ( Rec Incremento en toxicidad, sin beneficio adicional

Melanomas Biomarcadores en melanoma Ulceración tumoral y respuesta a interferón

Vacuna + HD IL-2 en Melanoma

Estudios seleccionado s como los más importantes

gp100 : 209 - 217 ( 210M)

Radioterapia a ganglios linfáticos Radioterapia adyuvante a campo comprometido

44 Estudios Estudios (2 (2 RCTs) RCTs) 11 Blockbuster Blockbuster in in the the making making

Terapia dirigida en Melanoma 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

El „Tema“ en melanoma es caracterizar la biología y aplicarla para el diseño de terapias

Otros avances

Ulceración puede ser predictiva IL-2 todavía puede tener un nicho RT a ganglios potencialmente útil

Biología Mutaciones de BRAF importantes Mutación del c-Kit importante

En el horizont Anti BRAF V600E: PLX4032 Anti c-Kit: Imatinib en subgrupos

Sarcomas Tumores de Células Gigantes del Hueso Denosumab

Tumores Desmoides

Estudios seleccionado s como los más importantes

Mutaciones de Beta Catenina son pronósticos

ASPS Cediranib es activo en Sarcomas de Tejidos Blandos Alveolar

55 Estudios Estudios (1 (1 RCT) RCT)

GIST Stop-and-go imatinib IGFr en GIST

RANKL Inhibition: Mechanism of Action O ste o cla s t p re cu rso r

RAN KL RAN K D e n o su m ab

Pre fu sio n o ste o cla s t

H o rm o n e s g ro w th fa cto rs C yto kin e s A p o p to tic o ste o cla s O ste o b la st t s

O ste o cla s t fo rm a tio n in h ib ite d O ste o cla st fu n ctio n a n d

B one Fo rm a tio n

Smith MR, et al. ASCO 2009. Abstract 9520

In h ib ite d B o n e R e so rp tio n

su rviva l in h ib ite d

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 §D e n o su m a b ( R A N K L a n ta g o n ista ) – e fica z e n G C T §C e d ira n ib ( A n tia n g io g é n ico ) – e fica z e n A S P S §S u ficie n te p a ra a p ro b a ció n p o r FD A / E M E A ? §S ó lo 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

El „Tema“ en sarcomas es caracterizar la biología y aplicarla para el diseño de terapias

Terapias dirigid

iRANKL (Denosumab) en GCT Antiangiogénicos (Cediranib) en ASPS

Biología Beta catenina implicada en tumores desmoides IGF1R implicado en subgrupo de GIST

Refinación Suspender transitoriamente el imatinib en GIST puede 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 cánceres cánceres biliares biliares §§Trastuzumab Trastuzumab ++ QT QT en en cáncer cáncer gástrico gástrico Her2 Her2 positivo positivo §§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 de de metastásico metastásico aa adyuvancia… adyuvancia… §§

§§Letalidad Letalidad sintética sintética §§iPARPs iPARPs en en tumores tumores con con deficiencia deficiencia del del BRCA BRCA §§Inhibidores Inhibidores del del BRAF BRAF en en melanoma melanoma