Tumores RAS nativo: tratamiento 1ª línea€¦ · Among WT KRAS exon 2 patients, an additional 17%...

P. García Alfonso

Sr. Oncología Médica

HGU Gregorio Marañón de Madrid

Tumores RAS nativo: tratamiento 1ª línea

“ A favor del bevacizumab”

Bevacizumab4

Supervivencia global en el Cáncer

Colorrectal metastásico

Median OS

Tim

e (

mo

nth

s)

BSC

5-FU

30

20

10

0

Irinotecan1

Capecitabine2

Oxaliplatin3

Cetuximab5,6

1980s 1990s 2000s 2010

Panitumumab7

Aflibercept8

Regorafenib9*

*Not approved by the EMA or for use in the Czech Republic

1. Cunningham, et al. Lancet 1998; 2. Van Cutsem, et al. BJC 2004; 3. Rothenberg, et al. JCO 2003

4. Hurwitz, et al. NEJM 2004; 5. Cunningham, et al. NEJM 2004; 6. Van Cutsem, et al. NEJM 2009

7. Van Cutsem, et al. JCO 2007; 8. Van Cutsem, et al, JCO 2012; 9. Grothey, Van Cutsem, et al. Lancet 2012

2012 ESMO consensus guidelines

Schmoll HJ et al. Ann Oncol 2012;23:2479–516.

La efficacia depende de la primera línea

1. Maughan TS, et al. Lancet 2011;377:2103–2114; 2. Saltz LB, et al. J Clin Oncol 2008;26:2013–2019; 3. Bokemeyer C, et al. Ann Oncol 2011;22:1535–1546; 4. Hurwitz H, et al. New Engl J Med 2004;350:2335–2342;

5. Langer C, et al. ESMO 2008 (Abstract No. 385P); 6. Peeters M, et al. J Clin OncoI 2010;28:4706–4713;

7. Giantonio BJ, et al. J Clin Oncol 2007;25:1539‒1544; 8. Grothey A, et al. Lancet 2013;38:303–312;

9. Karapetis CS, et al. N Engl J Med 2008;359:1757‒1765

Parameter 1st line 2nd line Later lines

ORR (%)* 38.0–64.01,2 10.3–35.05,6 1.0–12.88,9

Median PFS

(months)* 8.3–10.63,4 4.0–7.35,7 1.9–3.78,9

Conclusion: 1st linea de tratamiento es crítica en la OS

*Range of results for targeted treatment arms of key Phase II and III trials (KRAS 12/13 wt for EGFR inhibitor trials)

¿Con que biológico empezamos?

Antiangiogénicos?

Anti-EGFR?

Cúal es la primera línea de tratamiento

más activa para pacientes con CCRm

1st line

2nd line

3rd line

Biomarcadores

predictivos

Disponibilidad de los

fármacos (costes)

Medicina

basada en la

evidencia.

Eficacia/

Toxicidad

Angiogenesis is mediated through the interaction

between VEGF and its receptors1–5

7

1. Ferrara. Endocr Rev 2004; 2. Hicklin, Ellis. JCO 2005; 3. Baka, et al. Expert Opin Ther Targets 2006; 4. Morabito, et al. Oncologist 2006; 5. de Vries, et al. Science

1992; 6. Bergers, Benjamin. Nat Rev Cancer 2003; 7. Jain. Science 2005; 8. Gerber, Ferrara. Cancer Res 2005; 9. Jain. Nat Med 2001; 10. Inoue, et al. Cancer Cell 2002;

11. Margolin. Curr Oncol Rep 2002; 12. Hu, et al. Am J Pathol 2002

VEGF

VEGF

receptor Facilitates survival of

existing endothelial cells1,2,6–8

Contributes to vascular

abnormalities1,2,6,7,9

The interaction of the VEGF ligand with VEGF receptors is a key mediator of angiogenesis

Stimulates new

vessel growth1,2,6–8,10

Increases vessel

permeability11,12

Eficacia de las combinaciones

de Bevacizumab

Bevacizumab for 1L treatment of mCRC: significant

benefit with different chemotherapy regimens in phase

III trials

1. Hurwitz, et al. NEJM 2004; 2. Saltz, et al. JCO 2008; 3. Tebbutt, et al. JCO 2010 4. Cunningham, et al. ASCO GI 2013;

Regimen

Tx

line N Post-study therapy

ORR

(%)

Median

PFS

(months)

Median

OS

(months)

IFL

IFL + bevacizumab1 1L 813 2L: ~50%

2L: ~50%

35

45*

6.2

10.6*

15.6

20.3*

XELOX/FOLFOX

XELOX/FOLFOX + bevacizumab2 1L 1,401

2L: 53%

2L: 46%

38

38

8.0

9.4*

19.9

21.3

Capecitabine

Capecitabine + bevacizumab3 1L 313 68%

62%

30

38

5.7

8.5*

18.9

18.9

Capecitabine

Capecitabine + bevacizumab4 1L 280 37%

37%

10

19*

5.1

9.1*

16.8

20.7

*Statistically significant difference vs the control arm

NR = not reported

Amplia experiencia - Datos de eficacia consistentes

en EECC

Supervivenci

a Global

Supervivencia

Libre de

progresión

1. Bevacizumab [package insert]. South San Francisco, CA: Genentech; 2011. 2. Nalluri SR, et al. JAMA.

2008;300;2277-2285. 3. Hurwitz H, et al. J Clin Oncol. 2011;29:1757-1764.

Adverse Event Incidence With Bev Across Indications,[1] %

Comments

Grade ≥ 3 ATE 2.6

Risk of ATE increased in pts 65 yrs of age or older or with ATE history

Grade 3/4 HTN 5-18* Patients should receive otherwise standard CV

prophylaxis and have BP monitored and managed

GI perforations 0.3-2.4

Grade ≥ 3 hemorrhagic event 1.2-4.6†

Bev not recommended for pts with serious hemorrhage or recent hemoptysis

Risk of major bleeding does not appear to be increased in pts receiving full-dose anticoagulation tx without other risk factors

Wound complications

15‡ Discontinue 4-8 wks before surgery; resume 6-8 wks

postsurgery

Potential for increased VTE risk controversial; increased risk noted in 1 study but not in others.[2,3]

*Predominantly grade 3. †May apply more to NSCLC. ‡When surgery conducted during bev therapy.

Bevacizumab-Associated Toxicity

TRIBE: phase III trial comparing bevacizumab +

FOLFOXIRI with bevacizumab + FOLFIRI

OLIVIA study design

Criteria for unresectability

Patients had to meet at least one of the following criteria:

– no upfront R0/R1 resection of all hepatic lesions possible

– less than 30% estimated residual liver after resection

– disease in contact with major vessels of the remnant liver

FDG-PET was performed to exclude extrahepatic metastases

Primary endpoint: overall resection rate (R0/R1/R2)

Previously untreated,

unresectable colorectal

cancer with metastases

confined to the liver

N=80 Bevacizumab + mFOLFOX6 Bevacizumab 5 mg/kg, oxaliplatin

85 mg/m2, folinic acid 400 mg/m2, bolus

5-FU 400 mg/m2 then 5-FU 2400

mg/m2 46-hr infusion on day 1 q2w

Bevacizumab + FOLFOXIRI Bevacizumab 5 mg/kg, oxaliplatin

85 mg/m2, irinotecan 165 mg/m2, folinic

acid 200 mg/m2 and 5-FU 3200 mg/m2

46-hr infusion on day 1 q2w

Stratification factors:

• Centre

• ECOG performance status

• No. of metastatic lesions

Randomization

1:1

OLIVIA: Resection and Response rate and PFS –

ITT population

Variable, n (%)

Bev +

FOLFOXI

RI

(n=41)

Bev +

mFOLFO

X-6

(n=39)

Differ

ence

(%)

P

valu

e

Resection

rate

R0/R1/R2* 25 (61.0) 19 (48.7) 12.3 0.27

1

R0/R1 21 (51.2) 13 (33.3) 17.9 0.10

6

R0 20 (48.8) 9 (23.1) 25.7 0.01

7

Overall

response rate 33 (80.5) 24 (61.5) 18.9

0.06

1

Utilización de Bevacizumab en primera línea de

CCRm

1st

line

3rd

line

FU FU + Bev Optional 1st line

Oxaliplatin-based 1st line Irinotecan-based 1st line Chemo-

triplet

4th

line Regorafenib*

2nd

line

FU/Ox FU/Ox/Iri FU/Ox + Bev FOLFOX +

Pan or Cet

(FOLF)IRI+

Pan/Cet

FU/Iri +

Bev Fu/Iri Pan/Cet ± Iri

or FU/Bev

Pan/Cet ± Iri FU+Bev

FOLFIRI +

Aflibercept

Regorafenib*

FU/Iri +

Cet FU/Iri FU/Iri + Bev

FU/Ox FOLFOX +

Cet (Pan)

Pan/Cet ± Iri FU + Bev

Regorafenib*

Regorafenib* Regorafenib*

FU/Ox+

Bev

Schmoll, et al. Ann Oncol 2012 *Not approved by the EMEA or for use in the Czech Republic

FU/Ox/Iri

+Bev *

*Falcone, et al. ASCO 2013

¿Qué aportan los tratamientos de

mantenimiento con bevacizumab ?

Tratamiento de Mantenimiento con Bevacizumab

Trial 1L 2L SLP1 SLP2 OS

MACRO XELOX - Beva XELOX - Beva NA 10.4 NA 21.1

XELOX - Beva Beva NA 9.6 NA 20.4

CAIRO-3 XELOX - Beva XEL - Beva

XELOX - Beva 8.5 19.8 21.7

XELOX - Beva Observ 4.1 15 18.2

SAKK Quimio- Beva Beva NA 9.5 NA 25.1

Quimio- Beva Observ NA 8.5 NA 22.8

TML Quimio- Beva Quimio- Beva 5.7 NA 9.8

Quimio- Beva Quimio 4.1 NA 11.2

Está indicado el tratamiento de mantenimiento hasta la

progresión. El estándar es bevacizumab más capecitabina

CAIRO3: maintenance Beva + capecitabine versus observation

Koopman, et al. ASCO 2013

• Phase III trial

• Primary endpoint: PFS after re-introduction = PFS2

• Secondary endpoints: PFS1, OS, TTP2, ORR, safety

• PFS2 was considered to be equal to PFS1 for patients in whom Avastin + XELOX was

not reintroduced after PFS1 for any reason

Previously

untreated

mCRC

(n=558)

R Beva +

XELOX

(x6)

CR

PR

SD

Beva +

capecitabine

Observation Beva + XELOX PD2 PD1

PFS2 PFS1

TTP2

Arm A

Arm B

Beva + XELOX PD2 PD1

CAIRO3: resultados eficacia

Presented By Miriam Koopman, at 2014 ASCO Annual Meeting

Presented By Dirk Arnold, at 2014 ASCO Annual Meeting

Selección de Biológicos por biomarcadores

Bevacizumab independiente de RAS

…Hasta ahora los resultados de eficacia de Bevacizumab ha

resultado independiente del estado mutacional de Kras

PRIME study RAS analysis

KRAS, NRAS and BRAF mutation hotspots

Based on Douillard JY, et al. N Engl J Med 2013; 369:1023-34;

Oliner KS, et al. EJC 2013; 49 (suppl 3):abstract 2275 (and poster).

Percentages have been rounded; 7 patients harboured either KRAS or

NRAS codon 59 mutations

EXON 2 EXON 3 EXON 4 EXON 1

12 13 61 117 146

EXON 2 EXON 3 EXON 4 EXON 1

12 13 61 117 146

EXON 15 EXON 16 EXON 1

600

40% 5% 6%

4% 4% 0%

59

59

9%

Among WT KRAS exon 2 patients, an additional 17% of

tumours with RAS mutations were found

12 13 61 117 146 59

12 13 61 117 146 59

600

Overall RAS and BRAF

ascertainment rate: 89%

Overall RAS

ascertainment rate: 90%

NRAS

BRAF

KRAS

What data are available to support selection of

first-line therapy?

1st

line

3rd

line

FU FU + Bev Optional 1st line

Oxaliplatin-based 1st line Irinotecan-based 1st line Chemo-

triplet

4th

line Regorafenib*

2nd

line

FU/Ox FU/Ox/Iri FU/Ox + Bev FOLFOX +

*Pan or **Cet

(FOLF)IRI+

Pan/Cet

FU/Iri +

Bev Fu/Iri Pan/Cet ± Iri

or FU/Bev

Pan/Cet ± Iri FU+Bev

FOLFIRI +

Aflibercept

Regorafenib*

FU/Iri +

Cet FU/Iri

FU/Iri +

Bev

FU/Ox FOLFOX +

Cet (Pan)

Pan/Cet ± Iri FU + Bev

Regorafenib*

Regorafenib* Regorafenib*

FU/Ox+

Bev

Schmoll, et al. Ann Oncol 2012 *Oliner, et al. ASCO 2013 **Primrose JN, et al. ASCO 2013

WT RAS

Pmab – QT

Oxali

WT RAS

Cetux – QT

Irinotecan

CALGB 80405

(phase III)

FIRE III

(phase III)

Untreated

KRAS WT mCRC

(n=1,100)

Bevacizumab +

FOLFOX or FOLFIRI

Cetuximab +

FOLFOX or FOLFIRI

R

PD

PD Primary endpoint: OS

Untreated,

unresectable

KRAS WT mCRC

(n=285)

Bevacizumab +

mFOLFOX6

Panitumumab +

mFOLFOX6

R

PEAK

(phase II)

Primary endpoint: ORR

Primary endpoint: PFS

PD

PD

Untreated

KRAS WT

mCRC

(n=520)

Bevacizumab +

FOLFIRI

Cetuximab +

FOLFIRI

R

PD

PD

Cross-trial comparisons have

limitations – are head-to-head trials

available?

PEAK study mFOLFOX6 + panitumumab or bevacizumab in 1st-line

treatment of WT KRAS exon 2 mCRC

Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 (and poster);

Protocol ID: 20070509; ClinicalTrials.gov identifier: NCT00819780. ORR, objective response rate; mFOLFOX6, modified FOLFOX6

Metastatic

CRC

WT KRAS exon 2

(n = 285)

Tumour Assessment Q8W (±7 days);

Treatment administered until

disease progression, death,

or withdrawal from study

1:1

mFOLFOX6 (Q2W) +

panitumumab 6 mg/kg (Q2W)

mFOLFOX6 (Q2W) +

bevacizumab 5 mg/kg (Q2W)

• Study endpoints: PFS (1°); OS, ORR, safety, exploratory biomarker analysis

• No formal hypothesis testing was planned

E

n

d

o

f

t

r

e

a

t

m

e

n

t

S

a

f

e

t y

f

o

l

l

o

w

u

p

P

o

s

t

t

r

e

a

t

m

e

n

t

f

o

l

l

o

w

u

p

E

n

d

o

f

s

t

u

d

y

30 days

(+ 3 days)

Every 3 months (±28 days)

until end of study

R

PEAK study RAS analysis: PFS

PEAK study RAS analysis: OS

FIRE-3 study design

Stintzing S, et al. Journal of clinical oncology 2014 32(suppl 3):abstr 445. Pres. at ASCO GI 2014

FIRE-3 study results


RAS: Evaluation of ORR


RAS: Evaluation of PFS


RAS: Evaluation of OS


CALGB/SWOG 80405: FINAL DESIGN

Presented By Alan Venook at 2014 ASCO Annual Meeting

CALGB/SWOG 80405: Statistics


CALGB/SWOG 80405: Overall Survival

CALGB/SWOG 80405: Progression-Free Survival (Investigator Determined)

CALGB/SWOG 80405: Overall Survival FOLFOX Treated

CALGB/SWOG 80405: Overall Survival FOLFIRI Treated

Grade 3-4 Toxicities

Conclusiones

La supervivencia global de la QT/Cetuximab no es diferente

de la de la QT/Bevacizuab en primera línea de tratamiento en

pacientes kras wt.

Ambas combinaciones puedes ser considerados opciones

terapéuticas en kras wt

La SG en ambas ramas es superior a 29 meses,

estableciéndose un nuevo baremo para esta enfermedad

Análisis detallado de subgrupos y de largos supervivientes

pueden ofrecer una valiosa información

Hay que esperar a los resultados del estudio evaluados por

RAS

CALGB 80405

(phase III)

FIRE III

(phase III)

Untreated

KRAS WT mCRC

(n=1,100)

Bevacizumab +

FOLFOX or FOLFIRI

Cetuximab +

FOLFOX or FOLFIRI

R

PD

PD Primary endpoint: OS

Untreated,

unresectable

KRAS WT mCRC

(n=285)

Bevacizumab +

mFOLFOX6

Panitumumab +

mFOLFOX6

R

PEAK

(phase II)

Primary endpoint: ORR

Primary endpoint: PFS

PD

PD

Untreated

KRAS WT

mCRC

(n=520)

Bevacizumab +

FOLFIRI

Cetuximab +

FOLFIRI

R

PD

PD

Evaluación KRAS: Negativos

Estudios fase III: Evaluación por RAS total

PEAK:

– RAS total : aumento de PFS

– Estudio fase II generador de hipótesis

FIRE

– RAS total negativo

– Incremento de OS!!

CALGB

– RAS total ???

Personalización en el Tratamiento del CRCm:

Consideraciones

Extensión de la enfermedad

Intención del tratamiento (paliativo vs potencialmente curativo)

Performance status Edad Comorbilidades Adyuvancia previa en 1

año Marcadores moleculares

Función de órgano: hepatica y renal

Riesgo de toxicidad: Enf coronaria o ACA activo, proteinuria, hemorragia activa, heridas no cicatrizadas, alergia a los mAc, neuropatia, Enfermedad inflamatoria intestinal, Gilberts

Conveniencia Costes/recursos Preferencias del paciente

A favor de los antiangiogénicos

Los estudios fase III/II y los meta-análisis confirman la

eficacia de los antiangiogénicos

Perfil de tolerabilidad adecuado

Bevacizumab incrementa la supervivencia

independientemente del estado de RAS

Los estudios comparativos con anti-EGFR en pacientes

seleccionados por KRAS no encuentran diferencias en

eficacia

Permiten abordajes terapéuticos que priorizan calidad de

vida

Pueden mejorar la tasa de R0 en pacientes con metástasis

hepáticas en esquemas de tripletes

Preferencia del paciente y de los efectos

secundarios

Antiangiogénicos?

Anti-EGFR?

¡ Muchas Gracias!

[email protected]

Tumores RAS nativo: tratamiento 1ª línea€¦ · Among WT KRAS exon 2 patients, an additional 17%...

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