OPTIMIZACIÓN TRATAMIENTO

ANTI-EGFR

Ruth Vera

Oncología Médica

OPTIMIZACIÓN TRATAMIENTO anti-EGFR

• OPTIMIZAR quiere decir:

• Buscar los mejores resultados

• Planificar una actividad para obtener los

mejores resultados

• Mejorar

• …

Type of tumor Tumors with EGFR

expression

Head and neck 90–100%

Colon 75–89%

Pancreas Up to 95%

Breast Up to 91%

Renal Up to 90%

NSCLC Up to 80%

Ovary Up to 77%

Bladder Up to 72%

Glioma Up to 63%

Lung

(NSCLC)

Colorectal

Head and neck

EXPRESIÓN DE EGFR

Importancia de la vía del EGFR en el Cáncer colorrectal

Survival

(anti-apoptosis)

Gene transcription

Cell cycle progression

MYC

MYC Cyclin D1

FOS JUN

P P

Cyclin D1

Angiogenesis Invasion and

metastasis

Chemotherapy/

radiotherapy resistance

Proliferation/

maturation

MAPK

RAS RAF SOS GRB2

PTEN AKT

STAT

PI3K pY

pY

Ligand AREG/EREG

EGFR-TK

pY

MEK

Meyerhardt JA & Mayer RJ. N Engl J Med 2005;352:476–487;

Venook A. Oncologist 2005;10:250–261

CRYSTAL study: OS

OS

est

imate

Months

54 42 48

23.5

20.0

0.0

0.2

0.4

0.6

0.8

1.0

18 0 6 12 24 30 36

FOLFIRI (n=350)

HR 0.79

p=0.0093

Cetuximab + FOLFIRI (n=316)

KRAS exon 2 wt

population1

54 42 48 18 0 6 12 24 30 36

28.4

20.2

0.0

0.2

0.4

0.6

0.8

1.0

Cetuximab + FOLFIRI (n=178)

FOLFIRI (n=189)

HR 0.69

p=0.0024

RAS wt population2

Adapted from 1. Van Cutsem E, et al. J Clin Oncol 2011;29:2011–2019

and 2.Ciardiello F, et al. ASCO 2014 (Abstract No. 3506)

Months

1. Douillard JY, et al. J Clin Oncol 2010;28:4697-705;

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

WT RAS, WT KRAS & NRAS exons 2/3/4

(includes 7 patients harbouring KRAS/NRAS codon 59 mutations)

WT KRAS exon 21

0

20

40

60

80

100

90

70

50

30

10

0 36 4 8 12 16 28 32 20 24

Events n (%)

Median (95% CI) months

Panitumumab + FOLFOX4 (n = 325)

165 (51) 23.9 (20.3–28.3)

FOLFOX4 (n = 331) 190 (57) 19.7 (17.6–22.6)

HR = 0.83 (95% CI, 0.67–1.02)

P = 0.072

Events n (%)

Median (95% CI) months

Panitumumab + FOLFOX4 (n = 259)

128 (49) 26.0 (21.7–30.4)

FOLFOX4 (n = 253) 148 (58) 20.2 (17.7–23.1)

Pro

po

rtio

n a

live

(%

)

Months

0 36 4 8 12 16 20

0

20

40

60

80

100

90

70

50

30

10

24 28 32

HR = 0.78 (95% CI, 0.62–0.99)

P = 0.043

Pro

po

rtio

n a

live

(%

)

Months

WT RAS2

PRIME study: OS

1. Ciardiello F, et. al. ASCO 2014 (Abstract No. 3506)

2. Van Cutsem E, et. al. J Clin Oncol 2011; 29:2011–2019

3. Douillard J-Y, et al. N Engl J Med 2013;369:1023–1034

4. Douillard JY, et. al. Ann Oncol 2014;25:1346–1355

Study Biomarker n OS HR (95% CI)

CRYSTAL1,2 KRAS 666 0.80 (0.67–0.95)

Anti-EGFR

+ CT vs CT

RAS 367 0.69 (0.54–0.88)

PRIME3,4 KRAS 656 0.83 (0.70–0.98)

RAS 512 0.78 (0.62–0.99)

1.0 2.0 0.1

Benefit with anti-EGFR Benefit without anti-EGFR

Choice of targeted therapy: A growing body of

evidence

Phase III studies in 1st line mCRC: OS

anti-EGFR vs anti-VEGF

FIRE-3 study: OS

KRAS exon 2 wt

population RAS wt population (84%)

1. Adapted from Heinemann V, et al. Lancet Oncol 2014;15:1065–1075

OS

est

imate

28.7

months

25.0

months

0.75

1.0

0.50

0.25

0.0

12 24 36 48 60 72

Months

HR 0.77

p=0.017

0

Cetuximab + FOLFIRI (n=297)

Bevacizumab + FOLFIRI (n=295)

Cetuximab + FOLFIRI (n=171)

Bevacizumab + FOLFIRI (n=171)

33.1

months

25.6

months

0.0

12 24 36 48 60 72

0.7

5

1.0

0.5

0

0.2

5

0.0

OS

est

imate

Months

HR 0.70

p=0.011

0

0

20

40

60

80

100

90

70

50

30

10

Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631 and poster).

*Stratified Cox proportional hazards model; No formal hypothesis testing

was planned; WT RAS, WT KRAS & NRAS exons 2/3/4

WT KRAS exon 2

Pro

po

rtio

n e

ve

nt-

fre

e (

%)

Months

0 36 4 8 12 16 28 32 20 24 40

HR* = 0.84 (95% CI, 0.64–1.11)

P = 0.22

WT RAS

Pro

po

rtio

n e

ve

nt-

fre

e (

%)

Months

HR* = 0.66 (95% CI, 0.46–0.95)

P = 0.03

0

20

40

60

80

100

90

70

50

30

10

0 32 4 8 12 16 20 24 28 36 40

Events n (%)

Median (95% CI) months

Panitumumab + mFOLFOX6 (n = 142)

100 (70) 10.9 (9.7–12.8)

Bevacizumab +

mFOLFOX6 (n = 143)

108 (76) 10.1 (9.0–12.0)

Events n (%)

Median (95% CI) months

Panitumumab + mFOLFOX6 (n = 88)

57 (65) 13.0 (10.9–15.1)

Bevacizumab + mFOLFOX6 (n = 82)

66 (80) 10.1 (9.0–12.7)

PEAK study: PFS

Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631 and poster).

*Stratified Cox proportional hazards model; No formal hypothesis testing

was planned; WT RAS, WT KRAS & NRAS exons 2/3/4;

NR, not reached

WT KRAS exon 2

Months

Pro

po

rtio

n a

live

(%

)

0

20

40

60

80

100

90

70

50

30

10

0 36 4 8 12 16 28 32 20 24 40

HR* = 0.62 (95% CI, 0.44–0.89)

P = 0.009

44

Events n (%)

Median (95% CI) months

Panitumumab + mFOLFOX6 (n = 142)

52 (37) 34.2 (26.6–NR)

Bevacizumab +

mFOLFOX6 (n = 143)

78 (55) 24.3 (21.0–29.2)

Events n (%)

Median (95% CI) months

Panitumumab + mFOLFOX6 (n = 88)

30 (34) 41.3 (28.8–41.3)

Bevacizumab + mFOLFOX6 (n = 82)

40 (49) 28.9 (23.9–31.3)

WT RAS

Months

Pro

po

rtio

n a

live

(%

)

HR* = 0.63 (95% CI, 0.39–1.02)

P = 0.058

0 32 4 8 12 16 20 24 28 36

0

20

40

60

80

100

90

70

50

30

10

44 40

PEAK study: OS

Phase III 80405 Trial: PFS

Lenz H et al. ESMO, 2014.

Lenz H et al. ESMO, 2014.

Phase III 80405 Trial: OS

Khattak et al. Clin Colorectal Cancer 2015

Summary of results

Khattak et al. Clin Colorectal Cancer 2015

ORR with RAS

Khattak et al. Clin Colorectal Cancer 2015

PFS with RAS

Khattak et al. Clin Colorectal Cancer 2015

OS with RAS

Circulating free DNA as biomarker and source for mutation detection in metastatic colorectal cancer. Spindler KL

RAS mutations vary between lesions in synchronous primary colorectal cancer: testing only one lesion is not sufficient to guide anti-EGFR treatment decisions. Oncoscience. 2015 Feb 9;2(2):125-30

Mutational analysis of circulating tumor cells from colorectal cancer patients and correlation with primary tumor tissue. PLoS One. 2015 Apr 22;10(4):e0123902

DETERMINACIÓN RAS: DÓNDE Y CUÁNDO ?

Se puede OPTIMIZAR mas el

tratamiento con anti-EGFR ?

• Además de la selección por RAS …

Como podemos OPTIMIZAR mas el

tratamiento con anti-EGFR ?

• Mut PI3K

• Pérdida expresión PTEN

• Amplif MET

• Amplif HER2

• Sobreex HER3

• Mut adquiridas

• Sobreex Ligandos EGFR

• …

Anti-EGFR + …

CONCLUSIONES

• “RAS story” como el mejor ejemplo de OPTIMIZACIÓN

• COMO y CUANDO ?

• Otros Biomarcadores

• Combinación con otros fármacos en pacientes con

mutaciones

• Manejo de Toxicidad cutánea