presentación de powerpoint · 2016. 5. 18. · prime study post-hoc analysis (ets and response)...

ETS y Dor: Tienen estos dos parámetros alguna

relevancia para la cirugía de las metástasis. ¿Cuáles y de qué tipo son los niveles de

evidencia?

Dra. Antonieta Salud

Hospital Universitario Arnau de Vilanova, Lleida

Cordoba, 13 de mayo de 2016

¿Cuál es la definición ETS y

DpR?

¿La ETS es un concepto nuevo?

¿Cuál es la necesidad de valorar su

potencial como biomarcadores?

Phase I trials

¿Técnicas para valorar la respuesta?

¿Aplicación de rutina?

Radiólogos

DpR analysis in the CRYSTAL and OPUS mCRC trials

Panitumumab

PRIME

PRIME study post-hoc analysis (ETS and response) PFS and OS by ETS (20% cut-off) at Week 8

(updated analysis)

Douillard JY, et al. Eur J Cancer 2015;51:1231−42.

†Includes patients with baseline and Week 8 tumour shrinkage data only; ‡Assessing the overall relationship between Week 8 tumour shrinkage and PFS at 6 months; §Assessing the overall relationship between Week 8 tumour shrinkage and OS at 2 years.

Panitumumab + FOLFOX4 FOLFOX4

ETS < 20% ≥ 20% < 20% ≥ 20%

n (%)† 61 (28) 158 (72) 96 (43) 125 (57)

Median PFS, months

(95% CI)

6.7

(5.4–9.9) 13.6

(12.0–15.7)

6.1

(5.3–8.0)

9.9

(8.0–11.1)

HR

(95% CI)

P-value

0.62

(0.45–0.85)

0.0031

0.67

(0.50–0.88)

0.0040

Phi coefficient‡ 0.31

Median OS, months

(95% CI)

12.6

(9.3–18.2) 32.5

(28.3–37.6)

15.2

(11.4–17.2)

26.0

(22.1–31.3)

HR

(95% CI)

P-value

0.47

(0.34–0.65)

< 0.0001

0.50

(0.37–0.66)

< 0.0001

Phi coefficient§ 0.34

WT RAS

PRIME study post-hoc analysis (ETS and response) PFS and OS by ETS (30% cut-off) at Week 8

(updated analysis)


†Includes patients with baseline and Week 8 tumour shrinkage data only; ‡Assessing the overall relationship between Week 8 tumour shrinkage and PFS at 6 months; §Assessing the overall relationship between Week 8 tumour shrinkage and OS at 2 years.

Panitumumab + FOLFOX4 FOLFOX4

ETS < 30% ≥ 30% < 30% ≥ 30%

n (%)† 89 (41) 130 (59) 138 (62) 83 (38)

Median PFS, months

(95% CI)

9.3

(6.7–10.7) 14.9

(12.8–18.6)

7.0

(5.7–7.8)

10.9

(9.3–11.7)

HR

(95% CI)

P-value

0.56

(0.42–0.76)

0.0001

0.62

(0.47–0.83)

0.0014

Phi coefficient‡ 0.30

Median OS, months

(95% CI)

18.2

(14.2–22.5) 34.5

(29.8–40.7)

16.0

(14.2–18.8)

30.7

(23.6–36.2)

HR

(95% CI)

P-value

0.52

(0.38–0.70)

< 0.0001

0.46

(0.34–0.63)

< 0.0001

Phi coefficient§ 0.33

WT RAS

PRIME study post-hoc analysis (ETS and response)

ETS and response outcomes: overall population (updated analysis)


DoR, duration of response; NE, not evaluable; TTR, time to response. *For patients assessed at baseline

and Week 8 only; †Descriptive P-value (Fisher exact test); ‡Data based on central tumour response

analysis set (panitumumab + FOLFOX4 n = 248; FOLFOX4 n = 246);§HR is for FOLFOX4

vs panitumumab + FOLFOX4 and favours FOLFOX4; #Descriptive P-value (Wald test).

Panitumumab + FOLFOX4

(n = 253)

FOLFOX4

(n = 252)

Tumour shrinkage data at Week 8,* n

(%) 219 (87) 221 (88)

ETS ≥ 30% at Week 8,* n (%) 130 (59) 83 (38)

% difference (95% CI)

P-value†

21.8 (12.7–30.9)

< 0.001

ETS ≥ 20% at Week 8,* n (%) 158 (72) 125 (57)


P-value†

15.6 (6.8–24.4)

< 0.001

Objective response‡, n (%) 150 (60) 115 (47)


P-value†

13.7 (5.0–22.4)

0.003

Median TTR‡, months 3.4 NE

HR§ (95% CI)

P-value#

0.65 (0.51–0.83)

0.0006

Median DoR‡, months 11.8 8.4

HR (95% CI)

P-value#

0.63 (0.46–0.85)

0.0027

WT RAS


ETS and response outcomes:

LLD subgroup (updated analysis)


LLD, liver-limited disease. *For patients assessed at baseline and Week 8 only; †Descriptive P-value (Fisher exact test); ‡Data based on central tumour response analysis set

(panitumumab + FOLFOX4 n = 248; FOLFOX4 n = 246);§HR is for FOLFOX4

vs panitumumab + FOLFOX4 and favours FOLFOX4; #Descriptive P-value (Wald test).

Panitumumab + FOLFOX4

(n = 48)

FOLFOX4

(n = 41)

Tumour shrinkage data at Week 8,* n (%) 43 (90) 35 (85)

ETS ≥ 30% at Week 8,* n (%) 34 (79) 18 (51)


P-value†

27.6 (7.1–48.2)

0.015

ETS ≥ 20% at Week 8,* n (%) 38 (88) 27 (77)


P-value†

11.2 (-5.7–28.1)

0.229 (NS)

Objective response‡, n (%) 38 (81) 27 (66)


P-value†

15.0 (-3.4–33.4)

0.146 (NS)

Median TTR‡, months 1.8 3.2

HR§ (95% CI)

P-value#

0.55 (0.33–0.90)

0.0171

Median DoR‡, months 15.0 8.8

HR (95% CI)

P-value#

0.60 (0.33–1.09)

0.0938 (NS)

WT RAS

PRIME study post-hoc analysis (ETS and response) Resection rates, PFS and OS outcomes:

overall population (updated analysis)


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

†Descriptive P-value (Fisher exact test); ‡Descriptive P-value (Wald test).

Panitumumab +

FOLFOX4

(n = 253)

FOLFOX4

(n = 252)

Any resection, n (%) 35 (14) 29 (12)


P-value†

2.3 (-3.5–8.1)

0.504 (NS)

Complete resection, n (%) 26 (10) 19 (8)


P-value†

2.7 (-2.2–7.7)

0.349 (NS)

Median PFS, months 11.1 8.7

HR (95% CI)

P-value‡

0.74 (0.61–0.89)

0.0015

Median OS, months 26.0 20.2

HR (95% CI)

P-value‡

0.76 (0.63–0.92)

0.0057

WT RAS

PRIME study post-hoc analysis (LLD) Resection rates, PFS and OS outcomes

(updated analysis)


†Descriptive P-value (Fisher exact test); ‡Descriptive P-value (Wald test)

Panitumumab +

FOLFOX4

(n = 48)

FOLFOX4

(n = 41)

Any resection, n (%) 16 (33) 11 (27)


P-value†

6.5 (-12.5–25.5)

0.644 (NS)

Complete resection, n (%) 15 (31) 7 (17)


P-value†

14.2 (-3.3–31.6)

0.145 (NS)

Median PFS, months 11.3 9.9

HR (95% CI)

P-value‡

0.75 (0.48–1.19)

0.2223 (NS)

Median OS, months 33.4

HR (95% CI)

P-value‡

0.71 (0.43–1.16)

0.1737 (NS)

WT RAS (LLD)

40.7

PRIME study post-hoc analysis (ETS and response) Mean (95% CI) percentage change in tumour load (sum of all target lesions)

(updated analysis)


DpR, depth of response; Pmab, panitumumab. †Tumour shrinkage at nadir versus baseline tumour load

(sum of the longest diameters of all target lesions).

Mean c

hange fro

m b

aselin

e (

%)

−40

−20

0

−60

Week number of measurement

−80

0 8 16 24 32 40 48 56

Panitumumab + FOLFOX4 (n = 236)

FOLFOX4 (n = 224)

−100

Median DpR†, %

(Q1, Q3)

46 (23, 66)

54 (31, 72) P = 0.0149

245

242

219

221

195

183

157

147

116

110

96

71

71

39

55

25

Patients at risk:

Pmab + FOLFOX4

FOLFOX4

WT RAS

Events, n

Median OS, months


16 57.4

FOLFOX4 (n = 29) 15 54.5


OS by resection status (updated analysis)

Douillard JY, et al. Eur J Cancer 2015;51:1231−42. Censor indicated by vertical bar.

Patients at risk:

Pmab + FOLFOX4

FOLFOX4

35

29

35

29

34

28

33

28

33

28

33

26

32

24

30

21

29

20

24

16

22

14

19

11

16

10

14

9

10

4

6

2

2

0

0

-

WT RAS: WITH resection

Ka

pla

n−

Me

ier

estim

ate

100

80

60

40

20

0

0 4 8 12 16 20 24 28

Months

32 36 40 44 48 52 56 60 64 68

HR = 0.66 (95% CI, 0.32–1.35)

P-value = 0.2534


OS by resection status (updated analysis)

Douillard JY, et al. Eur J Cancer 2015;51:1231−42. Censor indicated by vertical bar.

Patients at risk:

Pmab + FOLFOX4

FOLFOX4

218

223

207

200

175

178

152

148

135

123

110

98

95

80

82

67

67

56

59

44

47

32

37

23

33

20

23

16

11

9

8

6

3

2

0

1

Ka

pla

n−

Me

ier

estim

ate

100

80

60

40

20

0

0 4 8 12 16 20 24 28

Months

32 36 40 44 48 52 56 60 64 68

HR = 0.79 (95% CI, 0.64–0.96)

P-value = 0.0186

Events, n

Median OS, months


182 21.7

FOLFOX4 (n = 223) 202 18.1

WT RAS: WITHOUT resection

TRIBE: early tumour shrinkage (ETS) and

deepness of response (DoR)

Cremolini C, et al. Ann Oncol 2015

ETS 20%

(n=256)

ETS ≤20%

(n=187)

DoR > median

(n=241)

DoR ≤ median

(n=243)

Median PFS,

months 12.7 10.0 13.1 9.3

HR (95% CI) 0.66 (0.52–0.79) 0.61 (0.49–0.73)

p-value <0.0001 <0.0001

Median OS,

months 35.8 22.4 36.8 21.3

HR (95% CI) 0.54 (0.39–0.67) 0.47 (0.35–0.58)

p-value <0.0001 <0.0001

(n=208) (n=171) (n=201) (n=217)

Median PPS,

months 17.1 10.7 18.4 10.5

HR (95% CI) 0.64 (0.47–0.81) 0.58 (0.44–0.73)

p-value 0.0005 <0.0001

TRIBE: early tumour shrinkage (ETS) and deepness of

response (DoR) predict progression-free, post-

progression and overall survival

Cremolini C, et al. Ann Oncol 2015

p value unreported

NS

NS

NS

NS

¿Con qué biológicos se obtiene mayor ETS y DpR?

Antiangiogénicos

Anti-EGFR

Heinemann v, et al. Lancet Oncol 2014

Heinemann v, et al. Lancet Oncol 2014

FIRE- 3

PEAK study – OS final analysis Between-treatment comparisons of PFS and OS by ETS (20% cut-off) at

week 8 (WT RAS population)

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

aOdds ratio is defined as the odds of having ≥ 20% tumour shrinkage in the

panitumumab + mFOLFOX6 arm relative to the odds

in the bevacizumab + mFOLFOX6 arm.

ETS < 20% ETS ≥ 20%

Panitumumab

+ mFOLFOX6

Bevacizumab

+ mFOLFOX6

Panitumumab

+ mFOLFOX6

Bevacizumab

+ mFOLFOX6

n (%) 20 (25) 28 (38) 60 (75) 46 (62)

Odds ratioa (95% CI)

P-value

1.67 (0.78‒3.58)

0.21

Median PFS, months

(95% CI)

9.8

(4.2‒15.4)

9.5

(7.4‒12.7)

13.1

(10.9‒16.2)

11.3

(9.2‒13.6)

HR (95% CI)

P-value

0.99 (0.50‒1.95)

0.97

0.70 (0.45‒1.08)

0.11

Median OS, months

(95% CI)

21.2

(14.1‒41.2)

21.8

(15.3‒28.9)

43.4

(36.4‒55.4)

32.5

(27.7‒47.4)

HR (95% CI)

P-value

0.81 (0.42‒1.57)

0.53

0.73 (0.44‒1.19)

0.21

PEAK study – OS final analysis Between-treatment comparisons of PFS and OS by ETS (30% cut-off) at

week 8 (WT RAS population)

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

poster).

aOdds ratio is defined as the odds of having ≥ 30% tumour shrinkage in the

panitumumab + mFOLFOX6 arm relative to the odds

in the bevacizumab + mFOLFOX6 arm.

ETS < 30% ETS ≥ 30%

Panitumumab

+ mFOLFOX6

Bevacizumab

+ mFOLFOX6

Panitumumab

+ mFOLFOX6

Bevacizumab

+ mFOLFOX6

n (%) 29 (36) 41 (55) 51 (64) 33 (45)

Odds ratioa (95% CI)

P-value

1.99 (0.99‒4.10)

0.052

Median PFS, months

(95% CI)

11.6

(7.5‒15.4)

9.7

(7.5‒12.9) 13.0

(10.9‒18.1) 11.1

(9.0‒16.6)

HR (95% CI)

P-value

0.79 (0.45‒1.38)

0.40

0.74 (0.45‒1.23)

0.24

Median OS, months

(95% CI)

34.2

(17.5‒42.3)

23.9

(20.1‒29.0) 43.8

(36.4‒63.0) 35.1

(29.9‒NE)

HR (95% CI)

P-value

0.75 (0.43‒1.31)

0.31

0.77 (0.42‒1.42)

0.41

PEAK study – OS final analysis

DoR, TTR and DpR (WT RAS population)

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

aFor DoR, TTR and DpR analyses, n = 81 for the bevacizumab group;

bHRs are presented as panitumumab + mFOLFOX6 : bevacizumab + mFOLFOX6.

A value < 1.0 indicates a lower average event rate and longer time to

event for panitumumab + mFOLFOX6 relative to bevacizumab + mFOLFOX6. cFor treatment effect; dWilcoxon test.

Panitumumab

+ mFOLFOX6

(n = 88)

Bevacizumab

+ mFOLFOX6

(n = 82)a

DoR, months – median

(95% CI)

11.4

(10.0‒16.3)

9.0

(7.6‒9.5)

HRb (95% CI)

P-valuec

0.59 (0.39‒0.88)

0.011

TTR, months – median

(95% CI) 2.3

(1.9‒3.7)

3.8

(2.1‒5.7)

HRb (95% CI)

P-valuec

1.19 (0.81‒1.74)

0.37

DpR, % – median

(Q1, Q3)

65.0

(45.7, 89.5)

46.3

(29.5, 63.3)

P-valued 0.0018

A

1:1

FOLFOX4 (Q2W) +

panitumumab 6 mg/kg (Q2W)

FOLFIRI (Q2W) +

panitumumab 6 mg/kg (Q2W))

Tasa Respuesta Objetiva (TRO) (principal)

Tasa de Resección Hepática (THR),

Supervivencia Libre de Progresión (SLP),

Supervivencia Global (SG), Seguridad Global y

Perioperatoria

CCRm KRAS WT LLD con

metástasis (mt) no resecables y/o ≥4 mt y/o 1 mt>10

cm

N=80

Variables:

La evaluación tumoral se llevó a cabo cada 8 semanas durante la fase de tratamiento

ETS y DpR con panitumumab más FOLFOX4 o FOLFIRI como

tratamiento de primera línea en pacientes con cáncer colorrectal

con RASwt y LLD

Abad A, et al. Eur J Cancer 2015;51(Suppl 3):S1‒S810:abstract 2128 (and poster).

RESULTADOS

P-FOLFOX4

(N = 26)

P-FOLFIRI

(N = 21)

Total

(N = 47)

≥30%, n (%) 16 (61,5) 15 (71,4)† 31 (66,0)

SG, m, mediana (IC95%) NA (32,5–NA) 45,8 (35,1–NA) 45,8 (44,7–NA)

<30%, n (%) 10 (38,5) 6 (28,6) 16 (34,0)

SG, m, mediana (IC95%) 22,4 (3,7–39,0) 51,5 (6,5–51,5) 26,4 (10,7–51,5)

HR (IC95%) ≥30%vs<30%

(valor p)

0,21 (0,05–0,80)

(0,023)

0,62 (0,10–3,91)

(0,614)

0,28 (0,10–0,77)

(0,014)

≥20%, n (%) 20 (76,1) 17 (80,9)‡ 37 (78,7)

SG, m, mediana (IC95%) NA (17,8–NA) 51,5 (35,1–51,5) 51,5 (35,1–51,5)

<20%, n (%) 6 (23,1) 4 (19,1) 10 (21,3)

SG, m, mediana (IC95%) 31,7 (10,7–39,0) NA (6,5–NA) 26,4 (6,5–39,0)

HR (IC95%) ≥20% vs <20%

(valor p)

0,35 (0,10–1,24)

(0,103)

0,28 (0,05–1,75)

(0,175)

0,31 (0,1,–0,83)

(0,020)

†p vs P-FOLFOX4=0,477;‡p vs P-FOLFOX4=0,974; IC=intervalo de confianza; m=meses; NA= no alcanzada; SG=supervivencia global


RESULTADOS

P-FOLFOX4

(N = 27)

P-FOLFIRI

(N = 26)

Total

(N = 53)

Tiempo hasta respuesta, m, mediana

(IC95%) 2,2 (1,8–4,2) 1,9 (1,8–2,5)§ 2,0 (1,8–2,5)

Duración de la respuesta, m, mediana

(IC95%), pacientes con respuesta

confirmada (N)

17,6 (6,8–23,9)

(13)

11,2 (1,1–16,2)£

(11)

15,4 (9,6–19,1)

(24)

DpR, %, mediana [IQR]

47,1 (32,3–70,6)

(27)

48,8 (42,9–64,0)

(23)

48,3 (32,5–66,7)

(50)

Todos los pacientes (N)

Pacientes con respuesta

confirmada (N)

70,6 (56,0–91,5)

(13)

64,0 (47,6–80,0)

(11)

66,8 (55,0–81,4)

(24)

§p vs P-FOLFOX4=0,277;£p vs P-FOLFOX4=0,146;

IC=intervalo de confianza; m=meses

DpR= profundidad de la respuesta; SG= supervivencia global;

SLP= supervivencia libre de progresión

SLP SG

DpR

0,5608

< 0,0001

0,3563

0,011 Correlación de

Spearman

(valor p)


RESULTADOS En el total de pacientes, hubo más cirugías con ETS≥30% vs <30% (64,5% vs

31,2%,p=0.030). En ETS ≥ 20% < 20% fue 59.4% vs 30%; p= 0.194 (N/S). Asimismo, la cirugía se asoció con una mayor supervivencia (mediana: 51 meses vs

26 meses en pacientes sin cirugía). En el grupo total de pacientes, la resección

quirúrgica se asoció a mayor supervivencia.

HR: 0,20 (95% CI: 0,07-0,56);

P log-rank = 0,002

Cirugía Mediana, meses (IC95%): 51,5 (35,1, 51,5)

Sin cirugía Mediana, meses (IC95%): 26,5 (10,8, 39,0)

Por

cent

aje

libre

de

even

tos

(%)

Tiempo (meses)

N/S, not significant Abad A, et al. Eur J Cancer 2015;51(Suppl 3):S1‒S810:abstract 2128 (and poster).

PLANET study PFS and OS according to ETS (20% cut-off) at Week 8

(wtRAS population)

Abad A, et al. Eur J Cancer 2015;51(Suppl 3):S1‒S810:abstract 2128 (and

poster).

100

80

60

40

20

0

Months

Pro

po

rtio

n e

ve

nt-

fre

e (

%)

0 12 24 36

ETS,

%

Median, months

(95% CI)

≥ 20 14.8 (12.5–20.1)

< 20 6.1 (1.4–12.8)

HR = 0.32 (95% CI, 0.14–0.70)

Log-rank P = 0.005

100

80

60

40

20

0

Months

ETS,

%

Median, months

(95% CI)

≥ 20 51.5 (35.1–51.5)

< 20 26.5 (6.5–39.0)

HR = 0.31 (95% CI, 0.11–0.83)

Log-rank P = 0.020

0 12 24 36 48

PFS OS

PLANET study PFS and OS according to ETS (30% cut-off) at Week 8

(wtRAS population)

Abad A, et al. Eur J Cancer 2015;51(Suppl 3):S1‒S810:abstract 2128 (and poster). NE, not estimable.

100

80

60

40

20

0

Months

Pro

po

rtio

n e

ve

nt-

fre

e (

%)

0 12 24 36

100

80

60

40

20

0

Months

0 12 24 48 36

PFS OS

ETS,

%

Median, months

(95% CI)

≥ 30 18.6 (12.7–23.1)

< 30 9.1 (3.7–14.2)

HR = 0.41 (95% CI, 0.21–0.79)

Log-rank P = 0.008

HR = 0.28 (95% CI, 0.10–0.77)

Log-rank P = 0.014

ETS,

%

Median, months

(95% CI)

≥ 30 45.8 (44.8–NE)

< 30 26.5 (10.7–51.5)

Consistent efficacy and DpR in 4 1st line studies

0

10

20

30

40

50

60

70

80

PEAK1

46%

65%

De

pth

of re

sp

on

se

(D

pR

, %

)

Beva+mFOLFOX6

Pmab+mFOLFOX6

P=0.0018

PRIME2

46%

54%

FOLFOX4

Pmab+FOLFOX4

P=0.0149

PLANET3

64%

71%

Pmab+FOLFIRI

Pmab+FOLFOX6

P= NR

TRIBE4

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. Cremolini C et al. Annals of oncology 2015; 26:1188-1194.

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

(LLD)

1st Line

Note: Data shown are not from comparative studies and

must be interpreted with caution.

43,4%

37,8%

P=0.003

Beva+FOLFOXIRI

Beva+FOLFIRI

La evaluación por RECIST presenta

limitaciones para predecir

supervivencia

¿Puede ser ETS un objetivo

alternativo?

Si? Se necesita continuar con su evaluación

¿Qué hacer con los no ETS

respondedores?

Segundas oportunidades? Resección de M1 hepáticas tras 2ªL

- RR: 16 - 41%

Panitumumab+FOLFIRI (all-wt) 41%

Velour 19,8%

RAISE 13,4%

TML 5%

- Resección hepática:

Velour 7,7%

RAISE 4,5 %

- Datos pacientes España: FOLFIRI+Aflibercept -13 pts

R0 77%, R1 23%

OS: NA

RFS: 11.3 meses

46% Biológicos en 1L (15% anti-EGFR)

¿Qué hacer con la inmunoterapia?

Momtaz P et al. Pharmgenomics Pers Med 2014; 7: 357-365

Anti-CTLA-4/Anti-PD-1/Anti-PD-L-1 Mechanism of Action

Building the future of metastatic colorectal cancer

patient to patient

Relación ETS y DpR con otras

técnicas Biopsia Líquida

http://www.theawsc.com/2013/07/29/the-two-sides-of-online-advertising/

Building the future of metastatic colorectal cancer

patient to patient

http://2.bp.blogspot.com/-d4DZXawrkIU/TcmAbJigi0I/AAAAAAAAASI/_bhIvK5LbBo/s1600/1293604471132_f.jpg

presentación de powerpoint · 2016. 5. 18. · prime study post-hoc analysis (ets and response)...

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