“Estrategia terapeutica del cáncer colorrectal: Selección

individualizada del tratamiento”

P. García Alfonso

Jefe de Sección de Oncología Médica

HGU Gregorio Marañón de Madrid

Metastatic Colorectal Cancer

0 10 20 30 40 50

FOLFOXIRI-Bev 2wt

FOLFOX-Pani 2wt

FIRE Ras wt

CALGB

FOLFOX-Pani

FOLFIRI-Cetu

FOLFOX-Cetu

FOLFOX-Bev

FOLFOX->FOLFIRI

IFL-Bev

FOLFOX

FOLFIRI

IFL

5FU i.c.

5FU bolus

BSC

41,7 41,3

33,1 29

25,8 23,5

22,8 21,3

20,6 20,3

19,5 17,4

14,8 14,1

12,6 5

Mediana Sup FOLFOXIRI-Bev 2wt

FOLFOX-Pani 2wt

FIRE Ras wt

CALGB

FOLFOX-Pani

FOLFIRI-Cetu

FOLFOX-Cetu

FOLFOX-Bev

FOLFOX->FOLFIRI

IFL-Bev

FOLFOX

FOLFIRI

IFL

5FU i.c.

5FU bolus

BSC

ESMO GUIDELINES 2015

(1) Referencia: Van Cutsem, Arnold and Cervantes. Session XIX: Metastatic Colorectal Cancer. World Congress on Gastrointestinal Cancer

Características

del tumor (1) Presentación clínica:

Localización del tumor Carga tumoral

Edad Performance status Función del órgano Comorbilidades

Perfil de toxicidad Flexibilidad Factores socio- económicos Calidad de vida Preferecias y expectativas del paciente

Para la toma de decisión de la1L de tratamiento en CCRm

Medicina Personalizada significa:

Biología del tumor Estatus mutacional de RAS Estatus mutacional de BRAF

Tournigand C et al., J Clin Oncol 22:229-237, 2004

Overa

ll S

urv

ival

(%)

21.5 months

20.6 months

Significant improvement in

Trial Fluoropyrimidine Irinotecan or

oxaliplatin EGFR

inhibitor RR PFS OS

CRYSTAL Inf + bolus 5-FU Irinotecan Cetuximab + + +

COIN Inf + bolus 5-FU Oxaliplatin Cetuximab + + –

Capecitabine Oxaliplatin Cetuximab – – –

NORDIC Bolus 5-FU Oxaliplatin Cetuximab – – –

PRIME Inf + bolus 5-FU Oxaliplatin Panitumumab + + +

Resultados de los ensayos fase III con inhibidores de EGFR

Grothey & Lenz. J Clin Oncol 2012

Resultados de los ensayos fase III con Bevacizumab en

primera línea de CCRm

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; Falcone NE Med 2014

Regimen

Tx

line N Post-study therapy

ORR

(%)

Median

PFS

(months)

Median

OS

(months)

Dobletes

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

Monoterapia

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

12,1 vs 9,7 p 0,003

31 vs 25,8 p 0,054

Estudio TRIBE

508 pacientes CCR EIV

FOLFOXIRI + beva

FOLFIRI + beva

OR: 62.7 % vs 51.9%; p=0.025

Marcadores moleculares

Mutaciones RAS

RAS wild-type

KRAS codon 12 mutant

KRAS codon 13 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

KRAS codon 12 mutant

KRAS codon 13 mutant

Extended RAS wild-type

(2014) KRAS exon 2 wild-type

(2008)

OS con inhibidores de EGFR en CCRm RAS/KRAS exon 2 MT

EGFR inhibitors are authorised only for RAS WT mCRC Sorich, et al. Ann Oncol 2015

Meta-analysis of >5,000 patients from randomised clinical trials

20020408

20050181

CRYSTAL

OPUS

PICCOLO

PRIME

Summary

213

593

460

167

148

548

1.06 (0.79–1.42)

0.91 (0.76–1.10)

1.05 (0.86–1.28)

1.29 (0.91–1.84)

1.22 (0.85–1.76)

1.21 (1.01–1.45)

1.08 (0.97–1.21)

p=0.14

N Study OS

Hazard ratio (95% CI)

Any RAS MT

0.5 1 2

Favours no cetux/panit

Favours cetux/panit

184

486

397

136

103

440

1.02 (0.75–1.39)

0.94 (0.76–1.15)

1.03 (0.83–1.28)

1.29 (0.87–1.91)

1.05 (0.69–1.61)

1.15 (0.94–1.41)

1.05 (0.95–1.71)

p=0.32

N

KRAS exon 2 MT

0.5 1 2

Favours no cetux/panit

Favours cetux/panit

OS Hazard ratio (95% CI)

AVF2107g: OS con bevacizumab acorde a estado mutacional de KRAS

Hurwitz, et al. Oncologist 2009

1.0

0.8

0.6

0.4

0.2

0

0 15 25 30 5 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 30 5 10 20

13.6 19.9 27.7 17.6

BRAF MT se asocia con peor pronóstico

Seligmann, et al. ASCO 2015

1L treatment OS for BRAF MT vs BRAF WT

BRAF MT patients have a significantly shorter median OS in 1L; only 39% of BRAF MT patients vs 60% BRAF WT received 2L treatment

OS

esti

mat

e

Time (months)

0 6 12 18 24 30 36 42

0

0.25

0.50

0.75

1.00

OS

esti

mat

e

Time (months)

0 3 6 9 12 15 18 24

0

0.25

0.50

0.75

1.00

BRAF WT BRAF MT

HR=1.48 p<0.001

BRAF WT BRAF MT

HR=1.17 p=0.33

21

6.9 10.2 10.8 16.4

2L treatment OS for BRAF MT vs BRAF WT

OS con inhibidores de EGFR en CCRm BRAF MT

EGFR inhibitors are authorised only for RAS WT mCRC Pietrantonio, et al. Eur J Cancer 2015

Meta-analysis of randomised clinical trials of cetuximab or panitumumab

Bokemeyer 2012

Douillard 2013

Karapetis 2013

Seymour 2013

Peeters 2014

Stintzing 2014

Total (95% CI)

–0.478

–0.105

–0.174

0.61

–0.446

–0.139

Log (hazard ratio) Study

0.275

0.342

0.736

0.263

0.354

0.314

0.62 (0.36–1.06)

0.90 (0.46–1.76)

0.84 (0.20–3.56)

1.84 (1.10–3.08)

0.64 (0.32–1.28)

0.87 (0.47–1.61)

0.91 (0.62–1.34)

Hazard ratio (95% CI) SE

0.2 1 5

Favours control

Favours EGFR inhibitors

20.7

17.0

6.0

21.5

16.4

18.5

100.0

Weight (%)

Heterogeneity: Tau2=0.11; Chi2=10.09 df=5 (p=0.07); I2=50% Test for overall effect: Z=0.48 (p=0.63)

2 0.5

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 PROGRAM CTC 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 WT N = 240

60%

BRAF MUT o PI3K MUT

(n=46)

Design: Randomized Phase II

Primary 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 months

Secondary endpoint: TR, OS, R0 surgery, toxicity, CTC level basal, Pten

FOLFIRI

+

Cetuximab

N=23

R

FOLFIRI

+

Bevacizumab

N=23

VISNÚ

ESMO 2015: Consensus on treatment of advanced mCRC

Progressive disease Disease control Cytoreduction

(shrinkage) Progressive disease

Unusual, see publication CT + Bevacizumab CT + biological agent Triplet + Bevacizumab Combination +

Bevacizumab Doublet + anti-EGFR

Continue; maintenance, or pause

Continue; maintenance, or pause Continue

BSC

2L

FP +/- Bevacizumab Reduced dose doublet

Anti-EGFR

Cure

Surgery alone Surgery with perioperative/ postoperative CT

Unfit (but may be suitable) Unfit Fit

Cytoreduction Disease control

2L

Re-evaluation/assessment of response every 2-3 months

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

Draft

Van Cutsem, Arnold and Cervantes. Session XIX: Metastatic Colorectal Cancer. World Congress on Gastrointestinal Cancer, 2015

ESMO 2015: Consensus on treatment of advanced mCRC

Progressive disease Disease control Cytoreduction

(shrinkage) Progressive disease

Unusual, see publication CT + Bevacizumab CT + biological agent Triplet + Bevacizumab Combination +

Bevacizumab Doublet + anti-EGFR

Continue; maintenance, or pause

Continue; maintenance, or pause Continue

BSC

2L

FP +/- Bevacizumab Reduced dose doublet

Anti-EGFR

Cure

Surgery alone Surgery with perioperative/ postoperative CT

Unfit (but may be suitable) Unfit Fit

Cytoreduction Disease control

2L

Re-evaluation/assessment of response every 2-3 months

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

Draft

Van Cutsem, Arnold and Cervantes. Session XIX: Metastatic Colorectal Cancer. World Congress on Gastrointestinal Cancer, 2015

Metástasis Hepáticas Irresecables o Potencialmente resecables

CELIM: Cetuximab + FOLFOX o FOLFIRI en metástasis hepáticas de CCR irresecables o mas de 5 metástasis

PLANET study

Response rate and resectability

†percentages calculated over the total number of patients with surgical resection in each group; ORR: Objective response rate

(not confirmed*); *patients resected before response confirmation

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

Gruenberger, et al. Annals of Oncology 2014

Resection and response rates

% (95% CI)

Bev + FOLFOXIRI (n=41)

Bev + mFOLFOX6 (n=39)

Difference

p-value

Resection rate

R0/R1/R2a 61.0 (44.5–75.8) 48.7 (32.4–65.2) 12.3 (–11.0–35.5) 0.271

R0/R1 51.2 (35.1–67.1) 33.3 (19.1–50.2) 17.9 (–5.0–40.7) 0.106

R0 48.8 (32.9–64.9) 23.1 (11.1–39.3) 25.7 (3.9–47.5) 0.017

Overall response rate 80.5 (65.1–91.2) 61.5 (44.6–76.6) 18.9 (–2.1–40.0) 0.061

Intent to treat population. aOnly two-stage hepatectomy

Bridgewater, et al. ECC 2013. Abstract 2159

Tratamiento de Metástasis Hepáticas: Revaluación de la respuesta cada 2 meses

Citoreducción

RAS y BRAF wt

RAS mutado BRAF

mutado

Doblete + Anti-EGFR* Doblete o Triplete + Bevacizumab

Triplete + Bevacizumab

ESMO 2015: Consensus on treatment of advanced mCRC

Progressive disease Disease control Cytoreduction

(shrinkage) Progressive disease

Unusual, see publication CT + Bevacizumab CT + biological agent Triplet + Bevacizumab Combination +

Bevacizumab Doublet + anti-EGFR

Continue; maintenance, or pause

Continue; maintenance, or pause Continue

BSC

2L

FP +/- Bevacizumab Reduced dose doublet

Anti-EGFR

Cure

Surgery alone Surgery with perioperative/ postoperative CT

Unfit (but may be suitable) Unfit Fit

Cytoreduction Disease control

2L

Re-evaluation/assessment of response every 2-3 months

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

Draft

Van Cutsem, Arnold and Cervantes. Session XIX: Metastatic Colorectal Cancer. World Congress on Gastrointestinal Cancer, 2015

Phase 2 PEAK study mFOLFOX6 + panitumumab or bevacizumab in 1st-line treatment of

WT KRAS exon 2 mCRC

Schwartzberg LS, et al. J Clin Oncol 2014;32:2240−7;

Protocol ID: 20070509; ClinicalTrials.gov identifier: NCT00819780. mFOLFOX6, modified FOLFOX6.

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

• No formal hypothesis testing was planned

Follow-up • Survival: Q3M (± 28

days) • Safety: 30 days after

last study drug administration

mCRC WT KRAS exon 2 (n = 285)

Tumour assessment Q8W (± 7 days); Treatment administered until disease progression, unacceptable toxicity, death, or withdrawal from study

1:1

mFOLFOX6 (Q2W) +

panitumumab 6 mg/kg (Q2W)

mFOLFOX6 (Q2W) + bevacizumab 5 mg/kg (Q2W)

R

PEAK: PFS & OS WT KRASKRAS WT RAS

Schwartzberg LS. J Clin Oncol. 2014 Jul 20;32(21):2240-7

RAS WT

FIRE-3 study design

Heinemann V et al. Lancet 2014;.

Fire-3: Tasa de Respuestas

Heinemann V et al. Lancet 2014

FIRE-3: PFS and OS

Heinemann V et al. Lancet 2014

FIRE-3: Depth of Response (DpR) Correlates With OS

CALGB/SWOG 80405: <br /> FINAL DESIGN

Presented By Alan Venook at 2014 ASCO Annual Meeting

CALGB 80405: RAS-WT - Supervivencia Global

Lenz, et al. ESMO 2014. abstract 501O

31.2 32.0

% li

bre

de

eve

nto

s

Grupo N Mediana RR p (Eventos) (IC 95%) (IC 95%)

No. en riesgo Meses desde el ingreso al estudio

CALGB 80405 RAS-WT: Resultados de SLP

Lenz, et al. ESMO 2014. abstract 501O

% li

bre

de

eve

nto

s

Grupo N Mediana RR p (Eventos) (IC 95%) (IC 95%)

No. en riesgo Meses desde el ingreso al estudio

ORR: Chemo+cetux: 68,6% vs Chemo + Beva: 53,6% (p<0,01)

FIRE-3: diferencias en eficacia en tumores del lado derecho vs lado

izquierdo

Heinemann, et al. ASCO 2014

Cetuximab + FOLFIRI Bevacizumab + FOLFIRI

HR (95% CI) p value HR (95% CI) p value

OS 0.34 (0.20–0.57)

<0.0001 1.04 (0.60–1.81)

0.89

PFS 0.43 (0.27–0.68)

0.0003 1.13 (0.73–1.75)

0.059

Multivariate Cox regression analysis (OS and PFS): location (left- vs right-sided tumour)

Cetuximab + FOLFIRI (n=167)

Bevacizumab + FOLFIRI (n=166)

Right-sided (n=30)

Left-sided (n=137)

OR (p value)

Right-sided (n=39)

Left-sided (n=127)

OR (p value)

ORR, % 46.7 70.1 2.7 (0.019)

48.7 62.2 1.7 (0.14)

PFS, months 6.9 10.8 0.35 (>0.001) 8.8 10.5 0.69 (0.065)

OS, months 16.1 38.7 0.26 (<0.0001)

22.7 28.0 0.63 (0.034)

Effect of primary tumour location on outcomes

Tratamiento de mantenimiento

CAIRO-3: Cape-Bev Maintenance vs Observation

• Primary endpoint: PFS2

– Time from randomization to progression upon reintroduction of CAPOX-B

– PFS2 considered equal to PFS1 in patients who do not receive CAPOX-B again (for any reason)

• Median follow-up: 40 mos

Patients with

mCRC and SD or

better after 6

cycles CAPOX-B,

WHO PS 0-1

(N = 558)

Observation

(n = 279)

Capecitabine +

Bevacizumab

(n = 279)

PD

Reintroduce

CAPOX-B PD

PFS1 PFS2

OR

Any treatment,

including

CAPOX-B

PD

TT2PD

Koopman M, et al. ASCO 2013. Abstract 3502.

CAIRO3: Maintenance Cape-Beva

Meta-analisis Beva maintenance

Clin Colorectal Cancer 2015

PFS

OS

Opciones terapéuticas en segunda línea

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

42

Aflibercept

1. Adapted from Holash. Proc Natl Acad Sci. 2002;99:11393–11398. 2. Adapted from Tew. Clin Cancer Res. 2010;16:358–366.

Aflibercept

Tabernero et al. Eur J Cancer. 2011;47(2): Abstract 6LBA

RAISE: Ramucirumab en CCR

OR: 13.4% vs 12.5% p : 0.6

Antiangiogénicos en 2º línea

asociados a FOLFIRI

2º line: Anti-EGFR combination

Ciardielo F et al. Annals of Oncology Advanced Acess 2016

Cetuximab + 1L

FOLFIRI (n=153)

kras wt

Cetu + FOLFOX

FOLFOX

R

• Primary endpoint: PFS from randomisation

• Secondary endpoints: OS from randomisation, best ORR, safety

PD

PD

CAPRI: PFS wt/mutated

Opciones terapéuticas en tercera y cuarta línea

ASPECCT study

Panitumumab vs. cetuximab in 3rd-

line treatment of WT KRAS exon 2

mCRC (open-label, phase 3)

Price T, et al. EJC 2013; 49 (suppl 3):LBA 18 (and oral presentation); Protocol ID: 20080763; ClinicalTrials.gov identifier: NCT01001377. WT KRAS, WT KRAS in codons 12/13

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

• Crossover between arms during study treatment was not allowed

1:1

R

1:1

Panitumumab

6 mg/kg IV (Q2W)

Cetuximab

400 mg/m2 loading dose,

250 mg/m2 IV (QW)

Metastatic mCRC

WT KRAS exon 2

(n = 999)

S

u

r

v

i

v

a

l

PD

PD

ASPECCT study: OS (primary analysis)

Price T, et al. EJC 2013; 49 (suppl 3):LBA 18 (and oral presentation).

HR = 0.97 (95% CI, 0.84–1.11)

P = 0.0007

Z-score = -3.19

Retention score = 1.06 (95% CI, 0.82–1.29)

Events

n (%)

Median (95% CI)

months

Panitumumab

(n = 499) 383 (76.8) 10.4 (9.4–11.6)

Cetuximab

(n = 500) 392 (78.4) 10.0 (9.3–11.0)

Pro

port

ion a

live (

%)

100

90

70

60

80

50

40

30

20

10

0

Months

0 6 12 18 24 30 36

• Multicenter, randomized, double-blind, placebo-controlled, phase III

– Stratification: prior anti-VEGF therapy, time from diagnosis of metastatic disease, geographical region

• Global trial: 16 countries, 114 centers

• Recruitment: May 2010 to March 2011

Regorafenib: Estudio CORRECT

Regorafenib 160 mg daily

3 weeks on / 1 week off (4-week cycle)

n = 136

Placebo n = 68

Stratification

• Metastases: single vs multiple

• Time from mCRC diagnosis:

>18 vs <18 months

• All patients received best supportive care

• Treat until progression, unacceptable toxicity, or withdrawal

Asian patients with mCRC who progressed after standard

therapies 25 Centers: mainland China,

Hong Kong, South Korea, Taiwan, Vietnam

CONCUR trial design Clinicaltrials.gov NCT01584830

Primary endpoint: overall survival (OS) • One-sided alpha 0.2 and assumed 33.3% OS improvement

(HR=0.75 favoring regorafenib) with 154 events had 80% power

Secondary endpoints: progression-free survival,

response rate , disease control rate

R 2:1

J. Li, et al. WCGI 2014. Abstract O-0023. Presented at WCGI 2014, Barcelona, Spain. Kim TW et al Presented at ESMO 2014, 26 – 30 September, Madrid Li J et al. Lancet 2015

CORRECT CONCUR

SLP

SG

SLP

SG

Regorafenib 1.9 m

Placebo 1.7 m

Regorafenib 6.4 m

Placebo 5.0 m

Regorafenib 8.8 m

Placebo 6.3 m

Regorafenib 3.2 m

Placebo 1.7 m

Mayer RJ et al. NEJM 2015

TAS 102 EN CCR m REFRACTARIO, FASE III

• Mayer & Van Cutsem et al.

Exposure to as many agents as

possible prolongs OS

Adapted from Grothey & Sargent. JCO 2005

OS (months) = 13.2 + (3 drugs % x 0.1), R2=0.85

Infusional 5-FU/LV

+ irinotecan

Infusional 5-FU/LV

+ oxaliplatin

Bolus 5-FU/LV

+ irinotecan

Irinotecan

+ oxaliplatin

Bolus 5-FU/LV

LV5FU2

First-line therapy

Me

dia

n O

S (

mo

nth

s)

Patients with 3 drugs (%)

2007

22

21

20

19

18

17

16

15

14

13

12

0 10 20 30 40 50 60 70 80

p=0.0001

FOLFOXIRI

CAIRO

CR-SEQUENCE Planned study design

Unresectable

mCRC

WT RAS

R1

1:1

FOLFOX +

bevacizumab

FOLFOX +

panitumumab

N cycles until PD, toxicity or

conversion surgery FOLFIRI +

bevacizumab

FOLFIRI +

panitumumab

N cycles until PD or toxicity

R2

Investigator choice:

1st-line reintroduction

or

Regorafenib

or

other

FOLFIRI +

bevacizumab

Futuro en CCR

CRC consensus molecular subtypes characteristics

Liquid Biopsy

Can Targeting EGFR Overcome Resistance to BRAF + MEK Inhibitors in BRAFm CRC?

Presented By Chloe Atreya at 2015 ASCO Annual Meeting

Best Response With Confirmation <br />Percent Change from Baseline at Maximum Reduction in Tumor Measurement

Presented By Chloe Atreya at 2015 ASCO Annual Meeting

Pembrolizumab: 10m g/k cada 2 semanas iv

Pembrolizumab en CCRm con MSI

NR NR

2.2 m 5.0 m

HER2 como diana en CCRm: HERACLES trial: Lapatinib + Trastuzumab

• Primary endpoint was met with 8/23 objective responses (as per protocol, 6/27 needed to declare the study positive)

• Disease control rate (DCR): 78%

Siena, et al. ASCO 2015

Response n (%)

ORR 8 (34.7)

CR 1 (4.3)

PR 7 (30.4)

SD ≥4 months 7 (30.4)

SD <4 months 3 (13.0)

PD 5 (21.7)

Response rate TTP

Surv

ival

pro

bab

ility

Time (months)

1.0

0.6

0.4

0.2

0

0 3

HER2 3+ (95% CI: 1.8–NR)

HER2 2+ (95% CI: 1.9–NR)

0.8

15

p=ns

6 9 12

4.2 7.3

N: 54 previamente tratados HER2 +

¡ Muchas Gracias! pgarcaalfonso@gmail.com

¡ Muchas Gracias!

0 10 20 30 40 50

FOLFOXIRI-Bev 2wt

FOLFOX-Pani 2wt

FIRE Ras wt

CALGB

FOLFOX-Pani

FOLFIRI-Cetu

FOLFOX-Cetu

FOLFOX-Bev

FOLFOX->FOLFIRI

IFL-Bev

FOLFOX

FOLFIRI

IFL

5FU i.c.

5FU bolus

BSC

41,7 41,3

33,1 29

25,8 23,5

22,8 21,3

20,6 20,3

19,5 17,4

14,8 14,1

12,6 5

Mediana Sup FOLFOXIRI-Bev 2wt

FOLFOX-Pani 2wt

FIRE Ras wt

CALGB

FOLFOX-Pani

FOLFIRI-Cetu

FOLFOX-Cetu

FOLFOX-Bev

FOLFOX->FOLFIRI

IFL-Bev

FOLFOX

FOLFIRI

IFL

5FU i.c.

5FU bolus

BSC