diapositiva 1fire-3 did not meet its primary endpoint of significantly improving overall response...

12.6

Thymidylate synthase

>40

VEGF + triplet CT

>30

VEGF or EGFR + doublet CT

20.3

VEGF + CT22.8

EGFR + CT

0

10

20

30

40

50

Mas opciones terapéuticas y mejor selección de pacientesincrementa sustancialmente la supervivencia

Scheithauer, et al. BMJ 1993; Saltz, et al. N Engl J Med 2000 Douillard, et al. Lancet 2000; Goldberg, et al. J Clin Oncol 2004

Hurwitz, et al. N Engl J Med 2004; Falcone, et al. J Clin Oncol 2007; Saltz, et al. J Clin Oncol 2008 Bokemeyer, et al. Ann Oncol 2011; Van Cutsem, et al. J Clin Oncol 2011; Douillard, et al. Ann Oncol 2014

Heinemann, et al. Lancet Oncol 2014; Lenz, et al. ESMO 2014; Loupakis, et al. ASCO 2015

20151980s

Tim

e (

mo

nth

s)

ITT KRAS RAS RAS/BRAF

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 20104. Cunningham, et al. ASCO GI 2013; Falcone NE Med 2014

Regimen

Tx

line N Post-study therapy

ORR

(%)

Median

PFS

(months)

Median

OS

(months)

IFL

IFL + bevacizumab1 1L 8132L: ~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 31368%

62%

30

38

5.7

8.5*

18.9

18.9

Capecitabine

Capecitabine + bevacizumab4 1L 28037%

37%

10

19*

5.1

9.1*

16.8

20.7

FOLFIRI+ Bevacizumab

FOLFOXIRI + Bevacizumab 1L 508- 53

65*

9.7

12.2*

25.8

31

*Statistically significant difference vs the control arm NR = not reported

Meta-análisis de Bevacizumab en CCR

Hurwitz H et al. Oncologist 2013

Selección de Tratamiento

Marcadores Clínicos

Marcadores Moleculares

Factores socioeconómicos y preferencias del

paciente

Caracteristicasdel pacienteEdadPSComorbilidadesQT adyuvante

Características Tumorales Volumen tumoral- Posible cirugía

rescate- Síntomas y

agresividad- Localización

Biomarcadores

Grado histológico CEAMSIKRASNRASBRAF

Calidad de vidaPerfil de toxicidad

Localización tumoral

Marcadores moleculares

Subgrupos del RAS WT

RAS MUT/WT

BRAF MUT

MSI

RAS/BRAFWT

Colon Derecho

Mutaciones RAS

RAS wild-type

KRAS codon 12 mutant


KRAS Exon 3 mutant

KRAS Exon 4 mutant

NRAS Exon 2 mutant

NRAS Exon 3 mutant

NRAS Exon 4 mutant

KRAS Exon 2

KRAS wild-type



Extended RAS wild-type

(2014)KRAS exon 2 wild-type

(2008)

AVF2107g: OS con bevacizumab acordea estado mutacional de KRAS

Hurwitz, et al. Oncologist 2009

1.0

0.8

0.6

0.4

0.2

0

0 15 25 305 10 20

1.0

0.8

0.6

0.4

0.2

0

KRAS MT(n=78)

KRAS WT (n=152)

Time (months)

OS

es

tim

ate

OS

es

tim

ate

Time (months)

Bevacizumab + IFL (n=44)

Placebo + IFL (n=34)

HR=0.69; p=0.26

Bevacizumab + IFL (n=85)

Placebo + IFL (n=67)

HR=0.58; p=0.04

0 15 25 305 10 20

13.6 19.9 27.717.6

RAS MUTADO

Van Cutsem et al. Ann Oncol 2016

Zurich treatment algorithm for patients with unresectable metastatic disease (excluding those with

oligometastatic disease)

Category Fit patients*

Treatment goal Cytoreduction (tumour shrinkage) Disease control (control of progression)

Molecular profile

RAS WT RAS MT BRAF MT RAS WT RAS MT BRAF MT

First-line

Preferred choice(s)

CT doublet +

EGFR antibody‡,§

CT doublet + bevacizumab

FOLFOXIRI + bevacizumab

CT doublet +

bevacizumab

OR

CT doublet + EGFR

antibody‡

CT doublet

+ bevacizumab

FOLFOXIRI ±bevacizumab

Second choice

FOLFOXIRI ±bevacizumab

FOLFOXIRI + bevacizumab


FP + bevacizumab – CT doublet + bevacizumab

Third choice


FOLFOXIRI FOLFOXIRI – – –

Biomarcadores en 5 estudios randomizados de AIO

Modest DP et al. Annals of Oncology 2016

Urson P et al.

Guías ESMO 2016

Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016; Online Ann Oncol, July 2016

Meta-análisis BRAF mutado

TRIBE Predictive impact - OS

0 20 40 600

25

50

75

100

Months

Pe

rce

nt s

urv

iva

l

N

FOLFIRI + bev

Arm A

Median OS

FOLFOXIRI + bev

Arm B

Median OS

HR [95% CI]

ITT population 508 25.8 31.0 0.79 [0.63-1.00]

R&B evaluable 375 25.8 31.0 0.86 [0.65-1.12]

RAS mutated 218 23.1 30.8 0.86 [0.60-1.22]

BRAF mutated 28 10.8 19.1 0.55 [0.24-1.23]

All wt patients 129 34.4 41.7 0.85 [0.52-1.39]

RAS mutated – FOLFOXIRI plus bev

RAS mutated – FOLFIRI plus bev

BRAF mutated – FOLFOXIRI plus bev

BRAF mutated – FOLFIRI plus bev

All wt – FOLFOXIRI plus bev

All wt – FOLFIRI plus bev

VISNÚ PROGRAMCTC Screening (n= 750 pts)

47%

≥3 CTC

(n=350)

VISNÚ 1 (TTD-12-01)

FOLFOX

+

Avastin

(n = 193)

R

FOLFOXIRI

+

Bevacizumab

(n = 175)

FOLFOX

+

Bevacizumab

(n = 175)

Design Randomized Phase III

Primary endpoint: PFS (superiority 8 m vs 11,2 m, HR: 0.71)

Secondary endpoint: RR, OS. R0 surgery, toxicity, CTC level basal, KRAS, BRAF, PI3K, Pten

VISNÚ 2 (TTD-12-02)

KRAS

mut

(n=191)

53%

FOLFIRI

+

Cetuximab

N=97

< 3 CTC

(n=400)

BRAF WT, PI3K WT

(n=194)

R

FOLFIRI

+

Bevacizumab

N=97

KRAS WTN = 240

60%

BRAF MUT o PI3K MUT

(n=46)

Design: Randomized Phase IIPrimary endpoint: -Group without mutation: minimum value 8.5 months optimum value 13 months and 1 year PFS rate IC less than (+/-10%)- Group with mutation: minimum value 2,5 months optimum value 6 monthsSecondary endpoint: TR, OS, R0 surgery, toxicity, CTC level basal, Pten

FOLFIRI

+

Cetuximab

N=23

R

FOLFIRI

+

Bevacizumab

N=23

VISNÚ

INESTABILIDAD DE MICROSATÉLITES

Presented By Federico Innocenti at 2017 ASCO Annual Meeting

Genomic markers in metastatic CRC

BRAF V600EBRAF non-V600

MSIMSI + otherPOLE mut

HER2 ampl

MET ampl

Gene fusion

RAS mut +/-PIK3CA/PTEN

mut PIK3CA/PTEN mut

Wild-type

anti-EGFR

anti-BRAF + anti-EGFR/MEKPD1 inhibitors

double anti-HER2

Kinase inhibitors

45% 8%

26%

8%2%2%

1%

1%

2%

2%

2%

19

31%

24%

26%

Colon derecho 9%

10%

27%

56%

3%

15%

31%

51%

Colon Izquierdo

Recto

*Tumor location data are in stage I–IV CRC; survival after relapse data are in stage I–III CRC

1.00

0.75

0.50

0.25

0.00

Pro

po

rtio

n e

ven

t-fr

ee

0 12

meses

24 36 48 60 72

Supervivencia después de la Recurrencia (n=405)

CMS1

CMS4CMS3

HR (95% CI)P

valueCMS4 vs. CMS1

0.60 (0.40‒0.88)

9.04 E-02

CMS3 vs. CMS1

0.60 (0.38‒0.97)

3.71 E-02

CMS2 vs. CMS1

0.35 (0.24‒0.52)

1.26 E-07

Log-rank p-value: 4.01 E-07

Guinney J, et al. Nat Med 2015;21:1350–1356

Clasificación Molecular: CMS 2 es más frecuente en lado Izdo y es de mejor pronóstico

19%CMS2

1. Stintzing S, et al. ASCO 2017 (Abstract No. 3510);2. Lenz H-J, et al. ASCO 2017 (Abstract No. 3511);3. Heinemann V et al. Lancet Oncol 2014;15:1065–1075;4. Venook A, et al JAMA. 2017;317:2392-2401.

FIRE-3 did not meet its primary endpoint of significantly improving overall response rate (ORR) based on investigators’ read in patients with KRAS (exon 2) wt mCRC.3 The CALGB/SWOG 80405 study did not meet its primary endpoint of significantly improving overall survival in the cetuximab + CT arm vs bevacizumab + CT arm in patients with KRAS (exon 2) wt mCRC4

Diferente impacto del CMS en los estudios retrospectivos Fase III en CCRm RAS wt

AGITG MAX: Eficacia del Bevacizumab en adicción a la capecitabina según grupos CMS

Mooi J et al. Annals of Oncology 2018

• Características de los pacientes

Grupos ESMO 2016

OVERALL RESPONSE

OS PFS

Guías ESMO 2016

II-A

v

FOIB1 TRIBE2 OPAL3 STEAM4 MOMA5 CHARTA6

n=57 n=252 n=97 n=93 n=232* n=125

RegimenFOLFOXIRI/

Bev

FOLFIRI/Bev

+/- Oxa

FOLFOXIRI/

Bev

FU/Bev

maintenance

FOLFOXIRI/

Bev vs

FOLFIRI/Bev

FOLFOXIRI/

Bev

Bev ±metroCT

FOLFOX/Be

± IRI

Response rate 77% 65% 64% 60% 63% 70%

Disease control rate 100% 90% 87% 91% 91% N/A

Median PFS, months 13.1 12.3 11.1 11.9 9.5 12.0

Median OS, months 30.9 29.8 32.2 34.0 Too early Too early

* >70% patients with RAS or BRAF mutation

1. Masi et al. Lancet

Oncol 2010; 2.

Cremolini et al.

Lancet Oncol

2015

FOLFOXIRI + bev: consistent results

Cremolini C, et al Annals of Oncolgy 2016 27:843-849

Metaanálisis

FOLFOXIRI/BEVA EN PACIENTES CON METAS IRRESECABLES OBTIENE UN 40% de conversióny una ¼ p de los pacientes obtiene R0

Tomasello G etal. JAMA Oncol. 2017;3(7):e170278.

30

PHASE II TRIAL DESIGN

mCRC

Unresectable

1st-line

WT RAS**

Age ≥ 18 yrs

ECOG PS 0-1

(n=96)

Randomization:

6/2011 - 1/2017

R

Treatment until PD, resectability,

or to maximum 12 cycles

mFOLFOXIRI +panitumumab 6 mg/kg Q2W

N=63

Irinotecan 150 mg/m2***, oxaliplatin 85 mg/m2,

LV 200 mg/m2, 5-FU 3000 mg/m2 CIV;

Planned safety analysis after 10 patients

treated in panitumumab arm

FOLFOXIRI Q2WN=33

2:1If resectable:

Surgery, then

protocol treatment to

maximum 12 cycles

If CR/PR/SD after 12 cycles:

re-induction

(same combination)

recommended on PD

Strata:

Cohort 1: histologically confirmed and definitively inoperable or unresectable

Cohort 2: chance of secondary resection with curative intent (*pretreatment liver/tumor biopsy)

**Amendment in 11/2013 to include all RAS wild-type only

*

*

• 21 active centers in Germany

***Trial started with irinotecan 165 mg/m2 (n=2), first amendment to 130 mg/m2 (n=9) and final amendment to 150 mg/m2 (n=52)

CR = complete response; ECOG PS = Eastern Cooperative Oncology Group performance status; PD = progressive disease; PR = partial response; Q2W = every

2 weeks; R = randomization; RAS = rat-associated sarcoma virus gene; SD = stable disease; WT = wild-type.

1 cycle FOLFOXIRI prior R was allowed

Results: Objective Response Rate

87.3

60.6

90.6

68.0 70.0

37.5

86.0

64.7

85.7

22.2

Full Analysis Set by Tumor Sidedness by Genotype

N = 96Left

N = 78Right

N = 18RAS/BRAF wt

N = 60BRAF mut

N = 16

P = 0.004 P = 0.021 P = 0.345 P = 0.081 P = 0.041

OR = 4.47 OR = 4.52 OR = 3.89 OR = 3.36 OR = 21.0

95%CI 1.61 – 12.38 1.30 – 15.72 0.54 – 27.89 0.90 – 12.55 1.50 – 293.25

CI= confidence interval

Geissler M, et al. VOLFI: mFOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer (mCRC): A randomized phase II trial of the AIO (AIO-KRK-0109)

• Pacientes de mal pronóstico que necesitan una respuesta rápida

TRIBE: early tumour shrinkage (ETS) and deepness of response (DoR) by treatment arm (*Data updated)

1. *Cremolini et al., 2015, Ann Oncol

R

1:1

FOLFOX +

bev*

FOLFOXIRI

+ bev*

PD1

PD1

5FU/bev

5FU/bev

FOLFIRI +

bev*

FOLFOXIRI

+ bev*

5FU/bev

5FU/bev

*all repeated for 8 cycles (4 months)

followed by maintenance with 5FU/bev until PD

Primary endpoint: PFS2 – Target Accrual 620 – Accrual up to Aug 29, 2016: 442

PD2

PD2

TRIBE-2: Study Design

Previum

Med PFS: 2.2 meses

Med OS: 3.4 meses

CONCLUSION: 1.El estudio no cumple su objetivoPor cierre prematuro2.Baja actividad clínica en pacientes con mal pronóstico (células tumorales circulantes > 3, con RAS BRAF mutado)

Guías ESMO 2016

CAIRO3 study<br />study design

Presented By Cornelis Punt at 2015 ASCO Annual Meeting

CAIRO3: Maintenance Cape-Beva: PFS1 & PFS2

Simkens LH et al, Lancet 2015

Meta-analisis Beva maintenance

Clin Colorectal Cancer 2015

PFS

OS

XELAVIRI (AIO KRK0110)

Modest D et al. JCO 2018

No se demuestra la no inferioridad para iniciar con monoterapia. No se cumpleLa no inferioridad en RAS/BRAF WT. La escalada secuencial de QT puede valorarse en RAS mutado

• ¿Cual es la mejor secuencia?

Lancet Oncol 2013 Jan;14(1):29-37.

Median: BEV + CT 11.2 months, CT 9.8 months

Median: BEV + CT 5.7 months, CT 4.1 months

PRODIGE 18

Bennouna J et al Jama Oncology 2018

7.1 vs 5.6 mHR 0.71; 95% CI 0.5-1.02 p=0.06

15.8 vs 10.4 mHR 0.69 95% CI0.46-1.04 0.08

OR: 24.6 vs 31.8%

Anti-EGFR en 2º línea tratados con Beva en los 6 últimos meses

Hayashi K et al. Oncology 2018

• New RCT have to stratify by location

• If all the sequence matters we need prospective RCT based on molecular characteristics, in a dynamic scenario

• Primary endpoint: 2nd progression/exitus free rate. (PFS1+PFS2): 30 vs 20 months. Total of 332 patients

CR-SEQUENCE: Planned study design

▪ PD, progressive disease.

Unresectable

left-side

mCRC

WT RAS/

WT BRAF

R

FOLFOX +bevacizumab

FOLFOX +panitumumab

N cycles until PD, toxicity orconversion surgery

FOLFIRI +panitumumab

N cycles until PD or toxicity

FOLFIRI +bevacizumab

▪ SEQUENCE 29/03/2017

Pro

gressio

nP

rogre

ssion

Seq 1

Seq 2

Investigator choice:1st line

reintroductionOr

RegorafenibOr

Other

•Localización Tumoral

Embriología Factores ambientales

Clínica

Distribución de subtipos moleculares

Factores genéticos

Diferencias del cáncer de colon derecho vs izquierdo

ESMO primary tumour location pooled analysisPredictive analysis of tumour location for treatment effect on OS

(pooled analysis, right vs left)

Arnold D, et al. Ann Oncol 2017;28(8):1713-29 PTL, primary tumour location.

Study ‒ PTL

Deaths/evaluable, n

HR HR interaction (95% CI)CTx + anti-EGFR CTx ± bevacizumab

FIRE-3 – left (n = 306)2.08 (1.19–3.63); P = 0.01

FIRE-3 – right (n = 88)

CALGB 80405 – left (n = 325)1.77 (1.11–2.80); P = 0.02

CALGB 80405 – right (n = 149)

PEAK – left (n = 107)0.86 (0.33–2.25); P = 0.77

PEAK – right (n = 36)

CRYSTAL – left (n = 280)1.66 (0.93–2.97); P = 0.09

CRYSTAL – right (n = 84)

PRIME – left (n = 328)1.19 (0.71–2.00); P = 0.51

PRIME – right (n = 88)

20050181 – left (n = 298)1.19 (0.67–2.10); P = 0.55

20050181 – right (n = 70)

[1.50 (1.19–1.88); P < 0.001]

Total – left 591/844 629/800 0.75 (0.67–0.84); P < 0.001

Total – right 194/234 230/281 1.12 (0.87–1.45); P = 0.381

Between HR interaction heterogeneity: P = 0.47 5.01.00.2

Favours CTx + anti-EGFR Favours CTx ± bevacizumab

ESMO primary tumour location pooled analysisPredictive analysis of tumour location for treatment effect on

PFS (pooled analysis, right vs left)

Arnold D, et al. Ann Oncol 2017;28(8):1713-29NA, not available (number of event data not available for CRYSTAL

study).

Study ‒ PTL

Events/evaluable, n

HR HR interaction (95% CI)CTx + anti-EGFR CTx ± bevacizumab

FIRE-3 – left (n = 306)1.60 (0.96–2.66); P = 0.07


CALGB 80405 – left (n = 325)1.95 (1.27–3.00); P = 0.002

CALGB 80405 – right (n = 149)

PEAK – left (n = 107)1.54 (0.66–3.59); P = 0.32


CRYSTAL – left (n = 280)1.74 (0.84–3.59); P = 0.13


PRIME – left (n = 328)1.11 (0.67–1.84); P = 0.68


20050181 – left (n = 298)0.85 (0.48–1.51); P = 0.58

20050181 – right (n = 70)

[1.43 (1.14–1.80); P = 0.002]

Total – left NA/844 NA/800 0.78 (0.70–0.87); P < 0.001

Total – right NA/234 NA/281 1.12 (0.87–1.44); P = 0.365


Favours CTx + anti-EGFR Favours CTx ± bevacizumab

ESMO primary tumour location pooled analysisPredictive analysis of tumour location for treatment effect on

ORR (pooled analysis, right vs left)

Arnold D, et al. Ann Oncol 2017;28(8):1713-29

Study ‒ PTL

Responses/evaluable, n

OR OR interaction (95% CI)CTx + anti-EGFR CTx ± bevacizumab

FIRE-3 – left (n = 306)0.81 (0.31–2.13); P = 0.67


CALGB 80405 – left (n = 325)0.67 (0.34–1.35); P = 0.26

CALGB 80405 – right (n = 149)

PEAK – left (n = 107)1.32 (0.36–4.77); P = 0.67


CRYSTAL – left (n = 280)0.36 (0.13–1.04); P = 0.06


PRIME – left (n = 324)0.72 (0.29–1.74); P = 0.46


20050181 – left (n = 291)0.88 (0.09–8.84); P = 0.91

20050181 – right (n = 68)

[0.69 (0.46–1.04); P = 0.07]

Total – left 368/793 552/840 2.12 (1.77–2.55); P < 0.001

Total – right 97/277 98/232 1.47 (0.94–2.29); P = 0.089


Favours CTx + anti-EGFRFavours CTx ± bevacizumab

Patients who received bevacizumab in addition to chemo had superior outcomes, with the

effect appearing greatest in patients with right colon disease.

Wong H et al. Clinical Colorectal Cancer 2016

Salem M et al. Eur J

Goal / condition Molecular Preferred 1st line regimen

Cytoreduction all WT Left: Doublet/EGFRRight: FOLFOXIRI/beva (Doublet/EGFR)

RAS mut FOLFOXIRI/beva

BRAF mut FOLFOXIRI/beva

Disease stabilization

all WT Left: Doublet/EGFRRight: Doublet (FOLFOXIRI)/beva

RAS mut Doublet (FOLFOXIRI)/beva

BRAF mut FOLFOXIRI (Doublet)/beva

„frail“, or chosen sequential treatment

no BRAF ! Capecitabine or 5FU/beva

Incorporating primary tumour location

Arnold et al, Ann Oncol

‘17

FOLFIRI plus bev, left N= 129FOLFOXIRI plus bev, left N = 113FOLFIRI plus bev, right N = 44FOLFOXIRI plus bev, right N = 72

Left-sided: HR= 0.99 [95%CI: 0.73-1.35]

Right-sided: HR= 0.56 [95%CI: 0.37-0.85]

p for interaction=0.030

The TriBe Study, subgroups according to PTL

Cremolini et al, Annals of Oncology

20º8

Targeting VEGF in cancer immunity

1. Chen DS, Mellman I. Immunity. 2013;39:1-10. 2. Hegde PS, et al. Semin Cancer Biol (submitted). 59

A. Promotion

of

DC

maturation

B.

Normalisation

of tumour

vasculature

C. Reprogramming of the

tumour microenvironment

from immune-suppressive

to immune-permissive

Due to the multiple effects of VEGF on

the tumour immune microenvironment,

targeting VEGF with Beva enhances the

anti-cancer immune response1,2

Presented By Wallin et al at 2016 AACR Annual Meeting

Atezolizumab plus Bevacizumab and/or FOLFOX in mCRC:phase Ib

Ensayos clínicos con bevacizumabmás inhibidores chekpoint

Conclusiones

• Bevacizumab es eficaz en todos los subgrupos moleculares• Su eficacia es independiente de la localización del tumor

primario• En objetivo conversión y en BRAF mutado el esquema

recomendado es el TRIPLETE/Beva• El mantenimiento con 5FU/Beva ha demostrado incrementar

la PFS• La secuenciación antiangiogénica incrementa la supervivencia

global• La secuencia adecuada de anti-angiogénicos y antiEGFR está

por demostrar • Estudios pre-clínicos con bevacizumab demuestran un

aumento de la inmunogenicidad del tumor

¡ Muchas [email protected]

diapositiva 1fire-3 did not meet its primary endpoint of significantly improving overall response...

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