Supervivencia global en el Cáncer Colorrectal metastásico

(1)

(2)

Bevacizumab⁴

Supervivencia global en el Cáncer Colorrectal metastásico

Median OS

Time (months)

BSC

5-FU 30

20

10

0

Irinotecan¹

Capecitabine² Oxaliplatin³

Cetuximab^5,6

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

(3)

ESMO GUIDELINES 2014/2015

(4)

La eficacia depende de la primera línea

1st line

2nd line

3rd line

OR: 10.3-35%5,6 PFS: 4-7.3 m 5,7

OR: 1-12.8 % 8,9 PFS 1.9-3.7 m 8,9 OR: 38-64% 1,2

PFS 8.3-10.6 m 3,4

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

(5)

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

Características del tumor (1)

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

(6)

Presentación clínica:

Localización del tumor Carga tumoral

Para la toma de decisión de la1L de tratamiento en CCRm Medicina Personalizada significa:

(7)

Edad

Performance status Función del órgano Comorbilidades

Para la toma de decisión de la1L de tratamiento en CCRm Medicina Personalizada significa:

(8)

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:

(9)

La intensidad de la quimioterapia debe

modularse en función del paciente

(10)

La intensidad de la quimioterapia debe

modularse en función del paciente

(11)

La intensidad de la quimioterapia debe

modularse en función del paciente

(12)

La intensidad de la quimioterapia debe

modularse en función del paciente

(13)

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

(14)

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

(15)

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

(16)

TRIBE: Updated Overall Survival

Follow-up time (months)

Overall survival probability

0 6 12 18 24 30 36 42 48 54 60 66 72 78

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

5ys-OS rate 24.9% vs 12.4%

FOLFOXIRI + Bev N= 252 / 174 events

Median, months 25.8 29.8

HR (95% CI)

P- value (log-rank) p=0.030

FOLFIRI + Bev N= 256 / 200 events

HR: 0.80 [0.65-0.98]

median follow up: 48.1 mos

(17)

Tratamiento de mantenimiento

(18)

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.

(19)

(20)

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

AIO Quimio-Beva 5FU-Beva NA 6.4 6.8* NA

Quimio-Beva  Beva NA 4.8 6.5* NA

Qimio-Beva  No TTO NA 3.6 6.1* NA

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

* TFS: Tiempo a fracaso de tratamiento

(21)

0 10 20 30 40 50

Más opciones terapéuticas y mejor selección de

pacientes incrementa 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

(22)

12.6

Thymidylate

synthase 20.3

VEGF + CT

0 10 20 30 40 50

Más opciones terapéuticas y mejor selección de

pacientes incrementa sustancialmente la supervivencia

2015 1980s

Time (months)

ITT

(23)

12.6

Thymidylate

synthase 20.3

VEGF + CT

22.8

EGFR + CT

0 10 20 30 40 50

Más opciones terapéuticas y mejor selección de

pacientes incrementa sustancialmente la supervivencia

2015 1980s

Time (months)

ITT KRAS

(24)

12.6

Thymidylate synthase

>30

VEGF or EGFR + doublet CT

20.3

VEGF + CT

22.8

EGFR + CT

0 10 20 30 40 50

Más opciones terapéuticas y mejor selección de

pacientes incrementa sustancialmente la supervivencia

2015 1980s

Time (months)

ITT KRAS RAS

(25)

12.6

Thymidylate synthase

>40

VEGF + triplet CT

>30

VEGF or EGFR + doublet CT

20.3

VEGF + CT

22.8

EGFR + CT

0 10 20 30 40 50

Más opciones terapéuticas y mejor selección de

pacientes incrementa sustancialmente la supervivencia

2015 1980s

Time (months)

ITT KRAS RAS RAS/BRAF

(26)

Marcadores moleculares

(27)

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)

(28)

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 5 10 15 20 25 30

1.0

0.8

0.6

0.4

0.2

0

KRAS MT (n=78)

KRAS WT (n=152)

Time (months)

OS estimate

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 5 10 15 20 25 30

13.6 19.9 17.6 27.7

(29)

Bevacizumab independiente de RAS

…Hasta ahora los resultados de eficacia de Bevacizumab ha

resultado independiente del estado mutacional de Kras

(30)

Bevacizumab independiente de RAS

…Hasta ahora los resultados de eficacia de Bevacizumab ha

resultado independiente del estado mutacional de Kras

(31)

Mutaciones de BRAF en 1ª y 2ª línea de CCRm

Di Nicolantonio F, J Clin Oncol 2018; ² De Roock et al. Lancet Oncol 2010; ³Van Cutsem et al, J Clin Oncol 2011; ⁴Seymour MT et al, Proc ASCO 2011

Estudio Esquema BRAF

%

SG Braf mutado

SG BRAF nativo

CAIRO-2 CAIRO-2

CAPOX- Beva

CAPOX-Beva-Cetuximab

7% 15

15.2

24.6 21.5

CRYSTAL FOLFIRI 6% 10.3 21.6

CRYSTAL FLOFIRI-Cetu 14.1 25.1

NORDIK VII FLOX+/-Cetu 12% 9.5 22

COIN COIN

XELOX/FOLFOX XELOX/FOLFOX

10% 10

7.2

20.1 19.9

Estudio Esquema SG

200501181 Picollo

FOLFIRI+/- Pani IRI +/- Pani

Pani-FOLFIRI 5.7 FOLFIRIHR: 1.4 (95% IC 0.8- 2.39

5.7 4.7 (ns)

(32)

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 estimate

Time (months)

0 6 12 18 24 30 36 42

0 0.25 0.50 0.75 1.00

OS estimate

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

(33)

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

(34)

TRIBE: efecto del tratamiento en subgrupos moleculares

*p value for interaction Loupakis, et al. ASCO 2015

Previously untreated, unresectable mCRC

(N=508)

Bevacizumab + FOLFIRI*

(n=256)

Bevacizumab + FOLFOXIRI*

(n=252) R

Bevacizumab + 5-FU/LV

(n=114)

Bevacizumab + 5-FU/LV

(n=130)

PD

Induction Maintenance

*Up to 12 cycles

Median OS, months

n

Bevacizumab + FOLFIRI

Bevacizumab + FOLFOXIRI

HR

(95% CI) p value Intent to treat (ITT)

population 508 25.8 29.8 0.80 (0.65–0.98) 0.030

RAS and BRAF evaluable

population 357 24.9 28.6 0.84 (0.66–1.07) 0.159

RAS and BRAF WT 93 33.5 41.7 0.77 (0.46–1.27)

0.522*

RAS MT 236 23.9 27.3 0.88 (0.65–1.18)

BRAF MT 28 10.7 19.0 0.54 (0.24–1.20)

RAS WT 121 26.8 37.1 0.78 (0.51–1.20)

0.658*

RAS MT 236 23.9 27.3 0.88 (0.65–1.18)

(35)

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

(36)

ETS and DpR as potential predictors of survival

Adopted from Mansmann UR, et al. J Clin Oncol. 2013;suppl 4:abstract 427.

•

ETS predicts sensitivity to treatment

•

ETS predicts the potential DpR

•

DpR predicts OS

Time Under Treatment ETS

DpR (smallest tumor size)

OS

(37)

-120

CRYSTAL and OPUS: Cetuximab + CT increases DpR vs CT alone (KRAS wt)

Cetuximab + CT CT

Cetuximab + FOLFIRI

(n=315)

FOLFIRI (n=348) Median DpR

(95% CI)

50.9 (18.4, 78.6)

33.3 (8.0, 58.0)

p-value p<0.0001

Cetuximab + FOLFOX4

(n=82)

FOLFOX4 (n=96) Median DpR

(95% CI)

57.9 (24.0, 92.9)

30.7 (4.0, 55.9)

p-value p=0.0008

CRYSTAL: LD OPUS: LD

Tumor shrinkage

Tumor growth -80

-40 0 40 80

DpR (%)

Patients -120

-160 -200

-80 -40 0 40 80

DpR (%)

Patients -160

-200

Tumor shrinkage

Tumor growth

Mansmann UR, et al. ASCO GI 2013 (Abstract No. 427)

(38)

Consistent efficacy and DpR in 4 1 ^st line studies

0 10 20 30 40 50 60 70 80

PEAK¹

46%

65%

Depth of response (DpR, %)

Pmab+mFOLFOX6 Pmab+mFOLFOX6

P=0.0018

PRIME²

46%

54%

FOLFOX4 Pmab+FOLFOX4

p=0.0149

PLANET³

64%

71%

Pmab+FOLFIRI Pmab+FOLFOX6

p= NR

314⁴

36%

59%

Pmab+FOLFIRI (RAS-MT) Pmab+FOLFIRI (RAS-WT)

p= 0.018

1. Rivera F et al. ECC 2015. Abstract 2014 and poster.

2. Douillard JY et al. Eur J Cancer Oxf Engl 1990. 2015 Jul;51(10):1231–42.

3. Abad A et al. ECC 2015. Abstract 2128 and poster.

4. Karthaus M et al. ECC 2015, Abstract 2130 and poster.

Bev: Bevacizumab, DpR: Depth of response, LLD: Liver-limited disease, NR: not reported, Pmab: Panitumumab

(LLD)

1

^st

Line

Note: Data shown are not from comparative studies and must be interpreted with caution.

(39)

-100 -80 -60 -40 -20 0 20 40 60 80

-100 -80 -60 -40 -20 0 20 40 60

80

FOLFIRI + bevacizumab FOLFOXIRI + bevacizumab

62.7%

51.9%

FOLFOXIRI + bevacizumab FOLFIRI +

bevacizumab

441 patients (87% of the ITT) Tumour shrinkage ≥20% at 8

weeks

p=0.025

TRIBE: respuesta precoz y profundidad de la respuesta

Cremolini, et al. Ann Oncol 2015

(40)

-100 -80 -60 -40 -20 0 20 40 60 80

-100 -80 -60 -40 -20 0 20 40 60

80

FOLFIRI + bevacizumab FOLFOXIRI + bevacizumab

p=0.003 62.7%

51.9%

FOLFOXIRI + bevacizumab FOLFIRI +

bevacizumab

441 patients (87% of the ITT) Tumour shrinkage ≥20% at 8

weeks

p=0.025

TRIBE: respuesta precoz y profundidad de la respuesta

Cremolini, et al. Ann Oncol 2015

(41)

Group Clinical presentation Treatment goal Treatment intensity GROUP 0 Clearly R0-resectable liver and/or

lung metastases

Cure, decrease risk of relapse

Nothing or moderate (FOLFOX)

GROUP 1

Not R0-resectable liver and/or

lung metastases only, may become resectable after induction CT

Maximum tumor shrinkage

Upfront most active combination

GROUP 2

Multiple metastases/sites, with rapid progression and/or tumor-related symptoms

Clinically relevant tumor shrinkage as soon as possible,

control PD

Upfront active combination: at

least doublet

GROUP 3

Multiple metastases/sites with no option for resection and/or initially asymptomatic with limited risk for rapid deterioration

Prevent further progression, low

toxicity

Watchful waiting or sequential approach (triplet regimens only in selected patients)

Elección Terapeútica de la primera línea

Schmoll H-J, et al. Ann Oncol 2012;23:2479–2516 by permission of Oxford University Press

• CT, chemotherapy

• PD, progressive disease

(42)

Tratamiento de la enfermedad metastásica

WCGC 2015

(43)

Metástasis Hepáticas Irresecables o

Potencialmente resecables

(44)

CELIM: Cetuximab + FOLFOX o FOLFIRI en

metástasis hepáticas de CCR irresecables o

mas de 5 metástasis

(45)

PLANET study

Panitumumab + FOLFOX4 or FOLFIRI in patients with WT KRAS exon mCRC and LLD

Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P);

ClinicalTrials.gov identifier: NCT00885885.

RAS ascertainment rate: 83.1%.

WT RAS = WT KRAS/NRAS exons 2, 3, 4.

 Study endpoints: ORR for entire panitumumab + CT treatment period (1), PFS, OS, liver metastases resection rate, time to resection, safety, peri-operative safety

 Exploratory endpoint: protocol predefined RAS analysis

mCRC, LLD (n = 77)

Treatment until progression or resectability achieved Response evaluation Q8W

Panitumumab 6 mg/kg

(Q2W)

+ FOLFOX4

(Q2W)

Panitumumab 6 mg/kg

(Q2W)

+ FOLFIRI

(Q2W)

R

1:1

PD

Or additional surgery

Follow-up

• Q3 ±1M after safety evaluation (up to 36M)

• Safety: 30±3 days after last study drug administration

(46)

PLANET : Panitumumab + FOLFOX o FOLFIRI en metástasis potencialmente resecables (RAS wt)

Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P).

37.0%

(18.8−55.3)

n = 10 25.9%

(9.4−42.4) n = 7 69.2%

(51.5−87.0) n = 18

53.8%

(34.6−73.0) n = 14 52.8%

(39.4−66.3)

n = 28 39.6%

(26.4−52.8) n = 21

0%

20%

40%

60%

80%

100%

Surgical resection Resection rate (R0 + R1)

Panitumumab + FOLFOX4 (n = 27) Panitumumab + FOLFIRI (n = 26) Total (n = 53)

WT RAS

Perc entage of pati ents (95% CI)

0

20

40

60

80

100

(47)

Median, months (95% CI) Panitumumab

+ FOLFOX4

39.0 (26.4–NA)

Panitumumab + FOLFIRI

45.8 (32.8–51.5) Median, months

(95% CI) Panitumumab

+ FOLFOX4

12.8 (6.2–22.0)

Panitumumab + FOLFIRI

14.8 (7.1–18.7)

PLANET study RAS analysis PFS and OS

Abad A, et al. Ann Oncol 2014;25(Suppl 4):iv189 (poster 551P).

WT RAS

Time (months)

Percentage free of event

Wilcoxon P-value = 0.675

40 30

20 10

0 100

80 60 40 20

0

Time (months)

40 30

20 10

0 100

80 60 40 20 0

50 Wilcoxon P-value = 0.634

PFS OS

(48)

Bevacizumab en Neoadyuvancia y Conversión de Metástasis heáticas

 No incrementa la tasa de complicaciones quirúrgicas ni la afecta a la regeneración hepática

 Incremento en tasa de respuestas patológicas

 Disminuye la toxicidad sinusoidal del oxaliplatino

Masi, et al. Lancet Oncol 2010; Gruenberger, et al. JCO 2008; Wong, et al. Ann Oncol2011 Ribero et al. Cancer 2007; Kinger et al. Ann Surg Oncol 2010; Adams et al. ASCO 2013

Study Experimental arm n

R0 resection rate (%)

BOXER

³

Bevacizumab + XELOX 45 20

GONO

⁴

Bevacizumab + FOLFOXIRI 30 40

(49)

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

(50)

Resection and response rates

% (95% CI)

Bev + FOLFOXIRI (n=41)

Bev + mFOLFOX6

(n=39) Difference p-value

Resection rate

R0/R1/R2^a 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

(51)

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

(52)

Tratamiento de la enfermedad metastásica

RAS wt RAS mt BRAF mt

CT + agente biológico

CT+bevacizumab Triplete + bevacizumab

Control de la enfermedad (control de la progresión)

PERFIL MOLECULAR

Revaloración/ valoración de la respuesta cada 2-3 meses

WCGC 2015

(53)

Phase 2 PEAK study

mFOLFOX6 + panitumumab or bevacizumab in 1 ^st -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; ORR, objective response rate;

OS, overall survival; PFS, progression-free survival;

Q2W, every 2 weeks; Q8W, every 8 weeks; Q3M, every 3 months; WT, wild type.

 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

(54)

PEAK study

mFOLFOX6 + panitumumab or bevacizumab in 1 ^st -line treatment of WT KRAS mCRC

Rivera F, et al. Eur J Cancer 2015;51(Suppl 3):S1‒S810:abstract 2014 (and poster)

(55)

(56)

Fire-3: FOLFIRI/ Cetuximab vs FOLFIRI/ Bevacizumab: Tasa de Respuestas

Heinemann V et al. Lancet 2014

(57)

FIRE-3: PFS and OS

Heinemann V et al. Lancet 2014

+ 3.7 meses

+ 7.5 meses

(58)

Conclusión: La secuencias de

aplicación del tratamiento puede ser más importante que la propia

exposición de cada uno de los agentes. En tumores RAS wt, la primera línea con un anti-

EFGR parece representar una opción más favorable para la efectividad de las siguientes líneas de tratamiento, incluidos los antiangiogénicos.

(59)

CALGB 80405 RAS-WT: Quimioterapia / Cetu vs Quimioterapia/ Beva: Resultados de SG y SLP

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

(60)

0 20 40 60 80 100

Score (0-100 scale, higher scores represent better QOL)

Cetuximab + CT Bevacizumab + CT

p = 0.0546

EORTC Global QOL DSQL Skin Satisfaction

p<0.0001

Baseline Week 6

Month 3

Month 6

Month 9

Baseline Week 6

Month 3

Month 6

Month 9

CALGB 80405: Impacto en calidad de vida dermatológica

 Venook. 2014.

60

82% de los pacientes completaron el cuestionario a los 3-meses

(61)

Importancia de la localización del tumor primario en el CCR

Iacopetta, et al. Int J Cancer 2002; Brule, et al. ASCO 2013 Missiaglia, et al. ASCO 2013; Lee, et al. ESJO 2015

• Incidence: ~40% (increasing)

• Older patients

• Microsatellite instability

• BRAF mutations

• Worse prognosis

Right-sided tumours

• Incidence: ~60%

• Younger patients

• Predominantly WT

• Better prognosis

Left-sided tumours

(62)

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

Heinemann, et al. ASCO 2014

Cetuximab + FOLFIRI (n=167)

Bevacizumab + FOLFIRI (n=166)

Right-sided (n=30)

Left-sided (n=137)

OR (p value)

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

(63)

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)

Left-sided (n=137)

OR (p value)

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

(64)

Secuenciación de Biológicos en CCRm

CCRm

RAS MT BRAF MT RAS/BRAF WT

Beva+QT Beva/Aflib+

QT

Anti-EGFR +QT

Anti_EGFR +QT Beva/ + QT Aflib/ IRI

Beva +QT Anti-EGFR +QT QT+Beva

QT+

Beva Aflibercept

QT+

Beva

Otra QT + Beva/

Aflibercept

(65)

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

Median OS (months)

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

(66)

0 10 20 30 40 50

>40

2015

1980s 2020

Time (months)

¿Como mejorar la supervivencia en los próximos 5 años?

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

ITT KRAS RAS RAS/BRAF

(67)

0 10 20 30 40 50

>40

2015

1980s 2020

Time (months)

Mejor selección de pacientes

¿Como mejorar la supervivencia en los próximos 5 años?

ITT KRAS RAS RAS/BRAF MSI high

(68)

0 10 20 30 40 50

>40

2015

1980s 2020

Time (months)

Mejor selección de pacientes

• Anti-HER2

• MSI high

• Next generation anti-VEGF

• Anti-PDL1/PD1

• Anti-BRAF + anti-EGFR

Nuevos biomarcadores Nuevos fármacos

Reversión de resistencias

¿Como mejorar la supervivencia en los próximos 5 años?

ITT KRAS RAS RAS/BRAF MSI high

(69)

Clasificación molecular del CCR

Guinney J et al. Nature American 2015; Dienstmann R. J Clin Oncol 2004

Moving to Molecular Subtypes

(70)

Danila DC (MSKCC): The Cancer Journal 2011

Paget 1.889: seed and soil

OPORTUNIDAD: BIOPSIAS LÍQUIDAS CTC

DNA tumoral

(71)

Mutations in mCRC

Dienstmann, R, Salazar R, Tabernero J. Am Soc Clin Oncol Educ Book. 2014;91-99.

asco.org/edbook

(72)

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

Survival probability

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 peviamente tratados HER2 +

(73)

Target Therapy Phase Trial design Trial ID

Anti-PDL1

Atezolizumab (engineered IgG1,

no ADCC)

I Solid tumours NCT01375842

Ib Solid tumours (+ bevacizumab ± FOLFOX) NCT01633970 II mCRC (+ bevacizumab + fluoropyrimidine) NCT02291289 MEDI4736

(modified IgG1, no ADCC)

II mCRC NCT02227667

Anti-PD1

Nivolumab (IgG4)

I/II MSI-high mCRC (± ipilimumab) (CheckMate 142) NCT02060188 I/II Solid tumours (+ INCB24360) NCT02327078 I/II Solid tumours (+ chemotherapy) NCT02423954 I/II Solid tumours (+ varlilumab) NCT02335918

Pembrolizumab (IgG4, humanised)

I Solid tumours (+ aflibercept) NCT02298959

I/II GI cancers (+ mFOLFOX6) NCT02268825

I/II KRAS, BRAF, NRAS WT mCRC (+ cetuximab or

trastuzumab or trastuzumab emtansine) NCT02318901 II mCRC (+ radiotherapy or ablation) NCT02437071

II mCRC (+ mFOLFOX6) NCT02375672

II mCRC (+ azacitidine) NCT02260440

II MSI-positive/-negative CRC NCT01876511

Examples of anti-PDL1/PD1 therapies currently under investigation in CRC*

*Recruiting studies Clinicaltrials.gov

(74)

(75)

PD-1 Blockade in Tumors with Mismatch-Repair

Deficiency

(76)

Nuevos estudios en CCRm BRAF mutado

(77)

Clinical studies of monotherapy BRAF inhibitors have demonstrated limited durable activity in CRC, with a confirmed RR ~5%.

– Vemurafenib had RR ~ 5% in BRAFm CRC

– Dabrafenib had RR ~9% in BRAFm CRC.

EGFR can mediate resistance of BRAF MT CRC to BRAF inh.

Anti-EGFR treatment is most synergistic with BRAF inhibition

Corcoran et al., Cancer Discovery 2012 Prahallad et al., Nature 2012

BRAF Mutant mCRC

(78)

Phase 1/2 Study of the MEK Inhibitor Trametinib, BRAF Inhibitor Dabrafenib, and Anti-EGFR Antibody Panitumumab in Patients With BRAF V600E-Mutated Metastatic Colorectal Cancer

Presented By Chloe Atreya at 2015 ASCO Annual Meeting

(79)

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

(80)

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

(81)

Duration on Study

(82)

Anticuerpo dual con unión a Ang2 y VEGF-A : vanucizumab

NCT02141295, CT.gov

Anti-VEGF-A

= bevacizumab

Knobs into holes CH1–CL cross over

VEGF-A Ang2

Anti-Ang2

= LC06

Vanucizumab

(83)

Anticuerpo dual con unión a Ang2 y VEGF-A : vanucizumab

NCT02141295, CT.gov

Anti-VEGF-A

= bevacizumab

Knobs into holes CH1–CL cross over

VEGF-A Ang2

Anti-Ang2

= LC06

Vanucizumab

1L mCRC N=140

Bevacizumab + mFOLFOX6

Vanucizumab + mFOLFOX6

Bevacizumab + 5-FU/LV

R

Vanucizumab + 5-FU/LV

Induction (up to 8 cycles)

Maintenance (until PD)

McCAVE trial design

Open-label safety run-in with n=6–18 patients Primary endpoint: estimated HR for PFS

(84)

Other targets in mCRC: the MODUL trial

*Induction phase treatment is investigator’s choice Arnold, et al. Ann Oncol 2015

Induction phase*

FOLFOX + bevacizumab

or

followed by 5-FU/LV + bevacizumab

CR PR SD

Biomarker-driven maintenance phase

Treatment until PD

Primary endpoint for maintenance phase: PFS

Stratify for MSI-high

(85)

Other targets in mCRC: the MODUL trial

Induction phase*

or

CR PR SD

Cohort 1 BRAF^mut ^R

FP + cetuximab + vemurafenib FP + bevacizumab

(86)

Other targets in mCRC: the MODUL trial

Induction phase*

or

CR PR SD

Cohort 2

‘NO BM’ ^R

FP + bevacizumab + atezolizumab

FP + bevacizumab

(87)

Other targets in mCRC: the MODUL trial

Induction phase*

or

CR PR SD

Cohort 2

‘NO BM’ ^R

FP + bevacizumab + atezolizumab FP + bevacizumab

Under discussion