ESMO Preceptorship colorectal cancer - OncologyPRO |...

ESMO Preceptorship colorectal cancerSingapore 28-29th March 2015

Session VIThe role of EGFR inhibition in mCRC

JY DOUILLARD MD PhD

mCRC treatment: Role of the EGFR pathway

EGFR EGFR homodimer

RASGTP RAS

GDPRAF

MEK

ERK

ElkMyc

JNK

Jun

JNKK

PAK

NckRac

PLCγ

PKC

PTEN

PI3K

S6K

AKT

mTOR

ProliferationAnti-apoptosisAngiogenesisSurvivalMetastasis

Fos

EGF

TGF-α

Anti-EGFR monoclonal antibody(panitumumab†/cetuximab)

EGFR

†Berg M, Discov Med 2012;14:207−14;Freeman D, et al. J Clin Oncol 2008;26(15S):14536;Ciardiello F, Tortora G. Clin Cancer Res 2001;7:2958−70.

Schubbert S, et al. Nat Rev Cancer 2007;7:295–308; Foon KA, et al. Int J Radiat Oncol Biol Phys 2004;58:984–90;Berg M, Soreide K. Discov Med 2012;14:207–14; Custodio A, Feliu J. Crit Rev Oncol Hematol 2013;85:45–81.

Example signalling pathways, simplifiedfor illustrative purposes

WT, wild type; MT, mutant.

RAS proteins are predictive biomarkers foranti-EGFR mAbs

RASGDP

RASGTP

EGFR Dimer

EGF

P P

EGFR signalling via RAS

RAS effector pathways

e.g. Tumour proliferation

Attenuation of signalling

RAS WT

RASGDP

RASGTP

Anti-EGFR mAb

Anti-EGFR inhibition of EGFR signalling

Inhibition of tumour proliferation

RAS MT

Anti-EGFR mAb

Constitutive signalling

Tumour proliferation

RASGTP

Anti-EGFR monoclonal antibodies in mCRC

• 2 mAbs are available:

• CETUXIMAB1

– IgG1 Human:mouse mAb– Extensively evaluated in

CRC– Mediates ADCC in vitro– Administered weekly

• PANITUMUMAB2

– IgG2 fully human mAb– Extensively evaluated in

CRC– May activate C2 complement– Administered Q 2 weeks

They show an identical efficacy when compared Head to Head in late lineTolerance profile slightly differs in term of allergic reaction

ASPECCT trialOS (primary analysis)

•Price T, et al. Eur J Cancer 2013;49(Suppl 3):LBA 18 (and oral presentation).

HR = 0.97 (95% CI, 0.84–1.11) P = 0.0007Z-score = -3.19Retention score = 1.06 (95% CI, 0.82–1.29)

Eventsn (%)

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

porti

on a

live

(%)

10090

7060

80

50403020100

Months0 6 12 18 24 30 36

ASPECCT trialIncidence of ≥ grade 3 AEs of interest

•Price T, et al. Eur J Cancer 2013;49(Suppl 3):LBA 18 (and oral presentation).

Adverse events, n (%)Panitumumab

(n = 496)Cetuximab(n = 503)

Fatal AEsColon cancerOthers

29 (5.8)20 (4.0)9 (1.8)

50 (9.9)34 (6.8)16 (3.2)

Treatment-related fatal AEs 0 (0) 1 (0.2)

Skin and subcutaneous tissue AEsAny gradeGrade 3Grade 4Serious

430 (86.7)60 (12.1)

2 (0.4)1 (0.2)

440 (87.5)48 (9.5)

0 (0)0 (0)

HypomagnesaemiaAny gradeGrade 3Grade 4

143 (28.8)27 (5.4)9 (1.8)

95 (18.9)10 (2.0)3 (0.6)

Infusion reactionsAny gradeGrade 3Grade 4

14 (2.8)1 (0.2)0 (0)

63 (12.5)5 (1.0)4 (0.8)

DiarrhoeaAny gradeGrade 3Grade 4

91 (18.3)7 (1.4)3 (0.6)

89 (17.7)9 (1.8)0 (0.0)

Impact of extended RAS analysis vs.KrasExon 2 on anti-EGFR MoAb efficacy in mCRC

Data from the PRIME trial

Douillard J-Y, et al. J Clin Oncol 2010;28:4697–705;.

PRIME trialFOLFOX4 ± panitumumab in first-line treatment of mCRC

• Study endpoints: PFS (1º), OS, ORR, safety• Design amended to focus on prospective hypothesis testing

in the KRAS WT# stratum

mCRC(n = 1183)

R

1:1

End

of

treat

ment

Long-term

follow-upDisease assessment every 8 weeks

Panitumumab6 mg/kg (Q2W)

+FOLFOX4 (Q2W)

FOLFOX4 (Q2W)

PRIME: PFS by KRAS Mutation StatusWT KRAS MT KRAS

Eventsn (%)


Panitumumab + FOLFOX

199 (61) 9.6 (9.2–11.1)

FOLFOX 215 (65) 8.0 (7.5–9.3)

HR = 0.80 (95% CI: 0.66–0.97) P-value = 0.02

Eventsn (%)


Panitumumab + FOLFOX

167 (76) 7.3 (6.3 – 8.0)

FOLFOX 157 (72) 8.8 (7.7 – 9.4)

HR = 1.29 (95% CI: 1.04 – 1.62)P-value = 0.02

Months

Prop

ortio

n Ev

ent-F

ree

00%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Months

Prop

ortio

n Ev

ent-F

ree

00%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

PRIME: OS by KRAS Status WT KRAS MT KRAS

Su

rviv

al P

rob

ab

ility

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Events / N (%) Medianin Months

Panit.+FOLFOX 165 /325 ( 51 ) 23.9FOLFOX alone 190 /331 ( 57 ) 19.7

Subjects at risk:Panit.+FOLFOXFOLFOX alone

325 315 310 288 266 242 227 217 207 189 164 135 104 74 55 29 9 2 0331 320 301 281 265 242 223 207 188 170 145 116 77 56 36 21 9 3 0

Su

rviv

al P

rob

ab

ility

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Events / N (%) Medianin Months

Panit.+FOLFOX 152 /221 ( 69 ) 15.5FOLFOX alone 142 /219 ( 65 ) 19.3

Subjects at risk:Panit.+FOLFOXFOLFOX alone

221 211 199 183 168 145 125 114 100 91 76 58 37 29 18 10 4 0 0219 212 206 199 181 166 149 132 120 112 96 69 55 39 25 11 2 0 0

HR 0.83 (0.67-1.02) p=0.072

23.9 m

19.7 m

HR 1.24 (0.98-1.57) p=0.068

19.3 m

15.5 m

Benefit of anti EGFR MoAbsin Kras exon2 mCRC1 st line

1. Van Cutsem E, et al. N Engl J Med 2009; 360:1408-17, 2. Bokemeyer C, et al. Ann Onc 2011; doi:10.1093/annonc/mdq632, 3. Douillard JY, et al. J Clin Onc 2010;27: 4697-4705 (updated Jan 2013)

• .wt Kras Folfiri 1 Folfiri cetux Folfox 2 Folfox Cetux Folfox 3 Folfox Pani

RR % 43 57 p=0.0001 34 57 p=0.002 48 57 p=0.02

PFS m 8.4 9.9 HR 0.70*

7.2 8.3 HR 0.56*

8 9.6HR 0.80*

OS m 20 23.5HR 0.80*

18.5 22.8 HR 0.85**

19.4 23.8 HR 0.83*

mt Kras

RR% 36 31 52 34 0.02 40 41

PFS m 7.7 7.4 HR 1.17** 8.6 5.5 HR 1.72* 8.8 7.3 HR 1.29*

OS m 16.7 16.2 HR 1.03** 17.5 13.4 HR 1.29** 19.2 15.5 HR 1.16**

Three cellular RAS genes encode four highly homologous 21 kD proteins

Adapted from Schubbert S, et al. Nat Rev Cancer 2007; 7:295–308.

P loop Switch I Switch II

G domainHypervariableregion

KKKKKK CVIM

1 1881312 61

KRAS4B

C C CVLS

1 85 165 1891610 32 38 59 671312 61

HRAS

KRAS4AC CIIM

1 1891312 61

C CVVM

1 1891312 61

NRAS

Douillard J-Y, et al. N Engl J Med 2013;369:1023−34.Percentages have been rounded. 7 patients harboured either

KRAS or NRAS codon 59 mutations. RAS and BRAF ascertainment rate: 89%.

KRAS, NRAS and BRAF mutation hotspots in the PRIME trial

NRAS

KRAS

EXON 2 EXON 3 EXON 4EXON 1

12 13 117 146


1213 61 117 146

BRAF

EXON 15 EXON 16…EXON 1…

600

40% 4% 6%

3% 4% 0%59

8%

Among WT KRAS exon 2 patients, an additional17% of tumours with RAS mutations were found

12 13 61 117 14659

12 13 61 117 14659

600

Overall RASascertainment

rate: 90%

1. Douillard J-Y, et al. J Clin Oncol 2013;31(Suppl):abstract 3620 (and poster);2. Douillard J-Y, et al. N Engl J Med 2013;369:1023−34.

PRIME trial RAS primary analysisRAS status – prevalence of RAS mutations among 1,060

evaluable patients

48%§

PRIME RAS analysis2

(refinement of patient population by RAS mutation status)

MT

WT

PRIME (KRAS exon 2)1

40% 60%

MT KRAS (exons 3, 4)9.4%#

52%¶

MT NRAS (exons 2, 3, 4)7.5%‡

PRIME trial RAS analysisRefinement of patient population by WT RAS status

(primary analysis)

WT KRAS exon 21 WT RAS2

Panitumumab + FOLFOX4(n = 325)

FOLFOX4(n = 331)

Panitumumab + FOLFOX4(n = 259)

FOLFOX4(n = 253)

Median PFS, months 9.6 8.0 10.1 7.9

Hazard ratio(P-value)

0.80(P = 0.02)

0.72(P = 0.004)

Median OS, months 23.9 19.7 26.0 20.2


0.83(P = 0.072)

0.78(P = 0.043)

ORR*, %(95% CI)

55(50–61)

(n = 175)

48(42–53)

(n = 154)

59(52–65)

(n = 149)

46(40–53)

(n = 114)

Odds ratio(P-value)

1.35†

(P = 0.068)1.63‡

(P = 0.009)

1. Douillard J-Y, et al. J Clin Oncol 2010;28:4697−705;2. Douillard J-Y, et al. N Engl J Med 2013;369:1023−34;

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

PRIME trial RAS primary analysisOverall survival

0 2 4 6 8 10 12 14 16 18 2420 22 3626 28 30 32 34

Pro

porti

on a

live

(%)

10090

7060

80

5040302010

0

Months

HR = 0.78 (95% CI, 0.62–0.99) P = 0.043

Eventsn (%)


Panitumumab + FOLFOX4 (n = 259) 128 (49) 26.0 (21.7–30.4)

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

WT RAS

Douillard J-Y, et al. N Engl J Med 2013;369:1023−34,Predefined retrospective analysis.

Excludes 7 patients harbouring KRAS/NRAS codon 59 mutations.

PRIME trial RAS primary analysis RAS mutations predicted negative OS outcome

with panitumumab + FOLFOXMT RAS

0 2 4 6 8 10 12 14 16 18 2420 22 3426 28 30 32

Prop

ortio

n al

ive

(%)

10090

7060

80

50403020100

Months

HR = 1.25 (95% CI, 1.02–1.55) P = 0.034

Eventsn (%)

Median, months(95% CI)


FOLFOX4 (n = 276) 175 (63) 19.2 (16.7–21.8)

WT KRAS exon 2, other MT RAS

0 2 4 6 8 10 12 14 16 18 2420 22 3426 28 30 32

Prop

ortio

n al

ive

(%)

10090

7060

80

50403020100

Months

HR = 1.29 (95% CI, 0.79–2.10) P = 0.305

Eventsn (%)

Median, months (95% CI)


FOLFOX4 (n = 57) 33 (58) 18.3 (13.0–23.2)

R

CRYSTAL study designFOLFIRI + cetuximab

N=599

Stratification factors:ECOG performance status Region

Treatment until disease progression, unacceptable toxicity, withdrawal of consent

Irinotecan

5-FULV

FOLFIRI (q2w)

400 mg/m2 initial dose then 250 mg/m2 weekly

180 mg/m2, day 1

400 mg/m2 bolus, then2400 mg/m2 infusion over 46 h

200 mg/m2*, day 1

Cetuximab

N=1198(KRAS codon 12/13 WT, N=666)

R

FOLFIRIN=599

EGFR-expressing, previously untreated,

mCRC

*L-form; 400 mg/m2, racemic5-FU, 5-fluorouracil; ECOG, Eastern Cooperative Oncology Group; LV, leucovorin; R, randomization; WT, wild-type

Presented by: Eric Van Cutsem

Hazard ratios (HRs) for (A) overall and (B) progression-free survival according to tumor KRAS exon 2 and RAS mutation status.

Eric Van Cutsem et al. JCO 2015;33:692-700

©2015 by American Society of Clinical Oncology

Kras exon 2 All Ras

CRYSTAL PFS 0.70 0.56

OS 0.80 0.69

OPUS PFS 0.57 0.43

OS 0.86 0.83

PRIME PFS 0.80 0.72

OS 0.83 0.78

Improved outcome with better patient selection

Sorich MJ, et al. Ann Oncol. 2015;26:13-21.

Importance of Targeting the Right Population

New RASTotal

KRASExon 3

KRASExon 4

NRASExon 2

NRASExon 3

NRASExon 4

59 61 117 146 12 13 59 61 117 146

26.3% 5.9% 9.3% 6.8% 5.1% 0.8%

9.8% NR 3.7% 6.8% NR NE

17.6% 4.8% 5.0% 4.2% 3.0% 1.1%

20.5% 4.6% 7.9% 2.3% 5.8% 0.0%

17.4% 3.7% 5.6% 3.4% 4.1% 0.0%

16.0% 4.3% 4.9% 3.8% 2.0% 0.0%

20.1% 4.1% 7.7% 5.4% 5.9% 0.0%

8.4% 2.1% NE 0.9% 3.0% NE

14.7% 3.3% 5.6% 3.5% 2.8% 0.9%

19.9%(16.7%, 23.4%)

4.3%(3.3%, 5.5%)

6.7%(5.7%, 7.9%)

3.8%(3.0%, 4.8%)

4.8%(3.4%, 6.8%)

0.5%(0.2%, 1.2%)

PICCOLO

OPUS

20050181

20020408

PRIME

FIRE-3

PEAK

COIN

CRYSTAL

SUMMARY

Sorich MJ, et al. Ann Oncol. 2015;26:13-21.

Prevalence of New RAS Mutations Across Studies

Randomized trials Bevacizumab vs. anti-EGFR

FIRE-32,3

Patients with untreated WT KRAS mCRC*Phase III, n = 592

PEAK1

Patients with untreated WT KRAS mCRC*Phase II, n = 285

CALGB/SWOG 804054,5

Patients with untreated WT KRAS mCRC

Phase III, n ~ 1,200(after trial modification)

Cetuximab + FOLFOX/FOLFIRI

Bev + FOLFOX/FOLFIRI

*Arm closed to accrual as of 09/10/2009

*Prespecified RAS analysis also conducted

1. Schwartzberg LS, et al. J Clin Oncol. 2014;32:2240-2247; 2. Heinemann V, et al. Lancet Oncol. 2014;15:1065-1075; 3. Stintzing S, et al. Ann Oncol. 2014;25(suppl 4):abstract LBA11 (and oral presentation); 4. Venook AP, et al. J Clin Oncol. 2014;32(suppl 5):abstract LBA3 (and oral presentation); 5. Lenz H, et al. Ann Oncol. 2014;25(suppl 4):abstract 5010 (and oral presentation).

*Prespecified RAS analysis also conducted

Panitumumab + mFOLFOX6

Bev + mFOLFOX6

R

Cetuximab + FOLFIRI

Bev + FOLFIRI

R

R

Bev + cetuximab + FOLFOX/FOLFIRI*

Head-to-Head 1st-Line RASwt mCRC TrialsBevacizumab vs. anti-EGFR

This is for information only. Informal comparison as these are not head-to-head clinical trials.1. Schwartzberg LS, et al. J Clin Oncol. 2014;32:2240-2247; 2. Venook AP, et al. J Clin Oncol. 2014;32:5s(suppl):abstract LBA3 (and oral presentation); 3. Lenz H, et al. Ann Oncol. 2014;25(suppl 4):abstract 5010 (and oral presentation).

Study Regimen Pts (%) ORR (%) Median PFS, (mo) Median OS (mo)

PEAK1

RAS WT (KRAS, NRAS)mFOLFOX6 + panitmFOLFOX6 + bev

8882

63.6%60.5%

13.09.5

(P = 0.029)

41.328.9

(P = 0.058)

FIRE-32

RAS WT (KRAS, NRAS)FOLFIRI + cetuxFOLFIRI + bev

297295

72% 56.1%

(P = 0.003)

10.4 10.3

(P = 0.54)

33.125.6

(P = 0.011)

CALGB 804053

RAS WT (KRAS, NRAS)Chemo + cetuxChemo + bev

270256

68.6%53.8%

(P < 0.01)

11.411.3

(P = 0.31)

31.232

(P = 0.40)

Targeted agents in 1st-line WT RAS mCRC

HR 0.83 [0.73-0.94], p=0.003

FIRE3

PEAK

CALGB

favors anti-EGFR favors anti-VEGF

Present data 1st line use of EGFR antibodies prolongssurvival over bevacizumab in wtKRAS mCRC

Gunnar Folprecht „Highlights of the day“ ASCO 2014

Additional points to consider for the use of anti-EGFR

Early tumor response (ETS)Duration of response (DoR)Deepness/Depth of Response DpR)

Time since start of treatment

∆OS

ETSTumor nadir PFS

Tumor load at baseline

Lethal tumor

load

Depth of Response Correlates With Overall Survival

• ETS predicts sensitivityto treatment

• DpR predicts OS

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

Panitumumab(Pmab) + FOLFOX4 FOLFOX4 (Ffox)

Shrinkage < 30%Events, n 76 130Median OS, months 18.2 16.0HR (95% CI) (0.80 (0.60, 1.06)P-value 0.1249Shrinkage ≥ 30%Events, n 63 64Median OS, months 34.5 30.7HR (95% CI) 0.85 (0.61, 1.17)P-value 0.3082

Deepness of responsed

Median, % (Q1, Q3) P Value54 (31, 72) 0.014946 (23, 66)

Panitumumab (Pmab) + FOLFOX(n = 236)

FOLFOX4 (Ffox)(n = 224)

Mea

n Ch

ange

Fro

m

Base

line

(%)

Week Number of Measurement0 8 16 24 32 40 48 56

-100

-80

-60

-40

-20

0

Kapl

an-M

eier

Est

imat

e

Months

100908070605040302010

0

40 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68

Tumor Shrinkage and Response Outcomes in PRIME

• In this study, ≥ 30% tumor shrinkage at week 8 was not predictive of outcome in individual patients

Summary table of survival outcomes by tumor shrinkage at week 8 (overall; RAS wild-type patients)

Panitumumab + FOLFOX4FOLFOX4

Alone

Tumor shrinkage at week 8 < 30% ≥ 30% < 30% ≥ 30%

na (%) 89 (41) 130 (59) 138 (62) 83 (38)Median PFS 9.3 14.9 7.0 10.9(95% CI) – months (6.7, 10.7) (12.8, 18.6) (5.7, 7.8) (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 correlation coefficientb 0.30

Median OS 18.2 34.5 16.0 30.7(95% CI) – months (14.2, 22.5) (29.8, 40.7) (14.2, 18.8) (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 correlation coefficientc 0.33

Pmab < 30%Pmab ≥ 30%

Ffox < 30%Ffox ≥ 30%

Censor indicated by vertical bar |.

1- Douillard, JY. et al. Annals of Oncology. 2013; 24(suppl 4): Abstr 0024 (and poster).2- Douillard, JY. et al. Submitted to European Journal of Cancer in Nov, 2014.

PRIME trial RAS analysis Objective response and tumour shrinkage (RAS WT, LLD patients, updated analysis)

Peeters M, et al. Eur J Cancer 2013;49(Suppl 4):abstract MC13-0022 (and poster).

6679

0

20

40

60

80

100

Prop

ortio

n, %

Objective response Tumour shrinkage ≥ 30% at week 8#

51

79

0

20

40

60

80

100

Prop

ortio

n, %

FOLFOX4

Panitumumab + FOLFOX4

P = 0.231 P = 0.015

n = 41 n = 48 n = 35 n = 43

PRIME trial RAS analysis Metastasectomy and complete resection rates

(RAS WT, LLD patients, updated analysis)

Peeters M, et al. Eur J Cancer 2013;49(Suppl 4):abstract MC13-0022 (and poster).

9

15

0

5

10

15

Patie

nts,

n

7

14

0

5

10

15

Patie

nts,

n

all resections R0 resection*

P = 0.349 P = 0.216

FOLFOX4(n = 41)


(n = 48)

FOLFOX4(n = 41)


(n = 48)

YES NO

All resected pts 78% 41%

R0 resected pts 84% 41%

M. Peeters, JY Douillard et al ASCO-EORTC-NCI meeting Brussels 7-9 Novembre 2013

PRIME Liver Limited Disease RAS WT population: Impact of resection on 3 year survival (WT RAS)

FOLFOX-Panitumumab Folfox

55% 44%

3 year-survival rate

3 year-survival rate chemotherapy arm

Tumor Shrinkage and Response Outcomes in PEAK

Rivera F, et al. ASCO GI 2015; San Francisco, CA. Abstract 660.

PEAK: Mean percentage change from baseline in tumor load for RAS WT subjects

Pmab +mFOLFOX6

Bev + mFOLFOX6 p-value

ORR (median [95% CI]), (%)

65 (64–75)

62 (50–72) –

DoR (median [95% CI]), months

11.4 (9.7–13,6)

8.5(6.3–9.3) 0.0142

ETS, patients (%) 64 45 0.0232

DpR (median [IQR]) (%)65

(48–87)46

(29–62) 0.0007

Week Number of Measurement

Mea

n C

hang

e Fr

om B

asel

ine

(%)

0

–20

–40

–60

–80

–100

0 8 16 24 32 40 48 56

Treatment: PMAB and mFOLFOX6 Bev and mFOLFOX6

PEAK StudyFOLFOX+PANI

(n = 315)FOLFOX+BEV

(n = 348) P

Median DpR (95% CI) 65 (48-87) 46 (29-62) P < 0.0007

Median OS (95% CI) 41.3 (28.8–41.3) 28.9 (23.9–31.3) P < 0.058

PEAK Study: PFS according to ETS

F Rivera ASCOGI 2015 Abst 660

PEAK Study: Tumor Shrinkage with time


PEAK Study: Tumor Shrinkage impact on OS


Depth of Response Correlates With Overall Survival

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

CRYSTAL StudyCetuximab + FOLFIRI

(n = 315)FOLFIRI

(n = 348) PMedian DpR (95% CI) 50.9 (18.4–78.6) 33.2 (8.0–58.0) P < 0.0001Median OS (95% CI) 23.5 (21.2–26.3) 20.0 (17.4–21.7) P < 0.0093

Data are supported by analyses of the CRYSTAL trial demonstrating that tumor size reduction was significantly associated with OS

• ETS predicts sensitivity to treatment

• ETS predicts the potential DpR• DpR predicts OS

Time Under Treatment

ETS

DpR (smallest tumor size)

∆OS

Time since start of treatment

∆OS

ETSTumor nadir PFS

Tumor load at baseline

Lethal tumor

load

FIRE-3Depth of Response Correlated With Overall Survival

• ETS predicts sensitivityto treatment

• DpR predicts OS

DpR = depth of response, defined as maximal tumor shrinkage observed in a patient.Stintzing S, et al. Ann Oncol. 2014;25(suppl 4):abstract LBA11 (and oral presentation).

FIRE-3 FOLFIRI + cetuximab(n = 157)

FOLFIRI + bevacizumab(n = 173) P

Median DpR (95% CI) 48.9 32.2 P < 0.0001

Median OS (95% CI) 33.1 (24.5–39.4) 25.0 (23.0–28.1) P = 0.0056

Post-progression therapy

What is the impact of 2nd line on overall survival?Is there a preferred sequence of use for targeted agents?

PRIME study RAS analysis OS from Start of 1st-Line Therapy in WT RAS with Post-Progression Therapy

Peeters M, Douillard JY et al. Markers in Cancer: A joint meeting by ASCO, EORTC and NCI 2013 (Brussels, November 7-9). EJC 2013;49:Suppl 4:S17-18:Abstract MC13-0024. Available at http://www.eortc.be/temp/EJC%20abstract%20book.pdf Accessed 30 October 2013.

Overall

http://www.eortc.be/temp/EJC%20abstract%20book.pdf

PRIME study RAS analysis OS from Start of First-Line Therapy for WT RAS treated Post-Progression

With anti-VEGF Therapy Without anti-VEGF Therapy

Peeters M, Douillard JY et al. Markers in Cancer: A joint meeting by ASCO, EORTC and NCI 2013 (Brussels, November 7-9). EJC 2013;49:Suppl 4:S17-18:Abstract MC13-0024. Available at http://www.eortc.be/temp/EJC%20abstract%20book.pdf Accessed 30 October 2013.

http://www.eortc.be/temp/EJC%20abstract%20book.pdf

Fire-3 StudyOverall Survival* in 2nd-Line Population (KRAS exon 2 WT)

*From randomization to FIRE-3.Modest DP, et al. J Clin Oncol. 2014;32:5s(suppl):abstract 3558.

No. at riskCTX + cet 204 170 89 50 23 4CTX + bev 191 158 86 38 15 1

1.0

0.8

0.6

0.4

0.2

0.0

Time (months)

Ove

rall

Surv

ival

0 12 24 36 48 60

Groups according to 1st-line therapy FOLFIRI + cetuximab: 30.0 mo

FOLFIRI + bevacizumab: 25.9 mo

P (log rank): 0.017HR: 0.74 (0.58–0.95)

Braf V600E mutation in mCRC

• Braf mutations occur in 8-12% of patients with mCRC.

– They are in vast majority V600E mutations– They are mutually exclusive with RAS mutation and will be found in

RAS wt type patients

• Braf mutations are a poor prognostic factor in mCRC

Douillard J-Y, et al. N Engl J Med 2013;369:1023−34.NE, not estimable.

Predefined retrospective analysis.Includes 7 patients harbouring KRAS/NRAS codon 59 mutations.

PRIME trial RAS primary analysisBRAF mutations appeared to be prognostic

Panitumumab+ FOLFOX4 FOLFOX4 HR P-value

WT RAS/MT BRAF, n 24 29

Median PFS, months(95% CI)

6.1(3.7–10.7)

5.4(3.3–6.2)

0.58(0.29–1.15)

0.12

Median OS, months(95% CI)

10.5(6.4–18.9)

9.2(8.0–15.7)

0.90(0.46–1.76)

0.76

WT RAS/WT BRAF, n 228 218

Median PFS, months(95% CI)

10.8(9.4–12.4)

9.2(7.4–9.6)

0.68(0.54–0.87)

0.002

Median OS, months(95% CI)

28.3(23.7–NE)

20.9(18.4–23.8)

0.74(0.57–0.96)

0.02

The role of EGFR inhibition in mCRC

2nd and later lines data

20050181 studyFOLFIRI ± panitumumab in second-line treatment

of mCRC

• Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation).

Metastatic CRC(n = 1186)

R

1:1

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

Long

term

follow

upDisease assessment every 8 weeks

FOLFIRI (Q2W) +panitumumab 6 mg/kg

(Q2W)

FOLFIRI (Q2W)

End

of

treat

ment

Study 20050181 RAS analysis Prevalence of KRAS, NRAS and BRAF mutations

•Peeters M, et al. J Clin Oncol 2014; 32:5s (suppl):abstract 3568 (and poster).


12 13 61 117 146


1213 61 117 146

EXON 15 EXON 16EXON 1

600

44.9% 4.3% 7.6%

2.2% 5.5% 0%

59

59

8.2%

Among WT KRAS exon 2 patients, an additional 18% of tumours with RAS mutations were found

12 13 61 117 14659

12 13 61 117 14659

600Overall RASascertainment rate: 85%

NRAS

BRAF

KRAS

20050181 study RAS analysis PFS (primary analysis)

1. Peeters M, et al. J Clin Oncol 2010; 28:4706-4713;2. Peeters M, et al. J Clin Oncol 2014; 32:5s (suppl):abstract 3568 (and poster

WT KRAS exon 2*,1

0 202 4 6 8 14 1610 12

HR = 0.73 (95% CI, 0.59–0.90)Log-rank p-value = 0.004


Months

WT RAS#,2

18

Eventsn (%)


Panitumumab + FOLFIRI (n = 303)

178 (59) 5.9 (5.5–6.7)

FOLFIRI (n = 294) 203 (69) 3.9 (3.7–5.3)

Eventsn (%)



120 (58) 6.4 (5.5–7.4)

FOLFIRI (n = 213) 139 (65) 4.6 (3.7–5.6)

0

20

40

60

80

100

90

70

50

30

10

Prop

ortio

n ev

ent-

free

(%)

0 181 3 6 8 90

20

40

60

80

100

90

70

50

30

10

11 14 15

Prop

ortio

n ev

ent-

free

(%)

Months2 4 5 7 10 12 13 16 17

20050181 study RAS analysis OS (primary analysis)

1. Peeters M, et al. J Clin Oncol 2010; 28:4706-47132. Peeters M, et al. J Clin Oncol 2014; 32:5s (suppl):abstract 3568 (and poster).

WT KRAS exon 21

0 342 4 6 8 18 2010 16



Months Months

WT RAS2

2212 14 24 26 28 30 32

Eventsn (%)



130 (63) 16.2 (14.5–19.7)

FOLFIRI (n = 213) 143 (67) 13.9 (11.9–16.0)

Eventsn (%)



200 (66) 14.5 (13.0–16.0)

FOLFIRI (n = 294) 207 (70) 12.5 (11.2–14.2)

0

20

40

60

80

100

90

70

50

30

10

Prop

ortio

n al

ive

(%)

0

20

40

60

80

100

90

70

50

30

10

Prop

ortio

n al

ive

(%)

0 342 4 6 8 18 2010 16 2212 14 24 26 28 30 32

20050181 study RAS analysisRefinement of patient population by WT RAS status

1. Peeters M, et al. J Clin Oncol 2010; 28:4706-47132. Peeters M, et al. J Clin Oncol 2014; 32:5s (suppl):abstract 3568 (and poster).

WT KRAS exon 21 WT RAS2

Panitumumab+ FOLFIRI(n = 303)

FOLFIRI(n = 294)

Panitumumab+ FOLFIRI(n = 204)

FOLFIRI(n = 211)

Median PFS,months 5.9 3.9 6.4 4.4


0.73(P = 0.004)

0.695(P = 0.006)

Median OS, months

14.5 12.5 16.2 13.9


0.85(P = 0.12)

0.803(P = 0.08)

ORR, %(95% CI)

35(30–41)(n = 297)

10(7–14)

(n = 285)

41(32–48)

(n = 200)

10(6–15)

(n = 205)

PANITUMUMAB single agenttreatment of metastatic colorectal cancer

20020408 studyPanitumumab in 3rd-line treatment of metastatic CRC

76% of BSC alone patients entered crossover studyMetastatic

CRC (n = 463)

1:1

Follow

up

Optional panitumumabcrossover study(20030194; n = 176)

Panitumumab6.0 mg/kg (Q2W)

+ BSC (n = 231)

Best Supportive Care (BSC)

(n = 232)

PD

PD

• Study endpoints: PFS (1°); ORR (per mRECIST version 1.0), OS

• Analyses prespecified in statistical analysis plan

R

20020408 study RAS analysis KRAS and NRAS mutation hotspots in the 20020408 study

•Patterson SD, et al. J Clin Oncol 2013; 31 (suppl):abstract 3617 (and poster).

EXON 2* EXON 3 EXON 4EXON 1

KRAS12 13 61 117 146

5%5%43%


NRAS12 13 61 117 146

1%3%4%

18% additional mutations

1Patterson S et al ASCO 2013 Abst. 3617

Panitumumab vs BSC (408 study):Improved PFS with better Ras selection

Prop

ortio

n Ev

ent-

Free

0%

20%

40%

60%

80%

100%90%

70%

50%

30%

10%

0 844 12 60WeeksPatients at risk

124

119

Panitumumab + BSC (n=99)BSC alone (n = 114)

24 48 72 1008 16 20 28 32 36 40 44 52 58 64 68 76 80 88 92 96

Eventsn/N (%)

115/124 (93)114/119 (96)

Hazard ratio = 0.45(95% CI, 0.34 – 0.59)P value <0.001

Median weeks(95 % CI)

12.3 (8.3-16.1)7.3 (7.0-7.7)

Panitumumab+ BSCBSC alone

112

91

50

38

63

15

50

14

44

10

33

9

21

6

17

6

13

4

10

3

7

2

5

2

4

1

4

1

3

1

3

1

2

1

2

0

2

0

2

0

2

0

2

0

2

0

1

0

0

0

PFS in Patients With Wild-Type KRAS Exon 2 mCRC1

Prop

ortio

n Ev

ent-

Free

0%

20%

40%

60%

80%

100%90%

70%

50%

30%

10%


73

63


24 48 72 1008 16 20 28 32 36 40 44 52 56 64 68 78 80 88 92 96

Eventsn/N (%)

70/73 (96)61/63 (97)

Hazard ratio = 0.36 (95% CI, 0.25 – 0.52)P value <0.001


14.1 (10.3-23.3)7.3 (6.0-7.4)


65

46

50

17

40

5

32

5

29

4

25

3

15

6

12

3

10

2 2

7 4

2

4

2

3

1

3

1

2

1

2

1

1

0

1

0

1

0

1

0

1

0

1

0

1

0

0

0

PFS in Patients With Wild-Type RAS* mCRC

1

0

Prop

ortio

n Ev

ent-

Free

0%

20%

40%

60%

80%

100%90%

70%

50%

30%

10%


99

114


48 728 16 20 28 32 36 40 44 52 58 64 68 76 80

Eventsn/N (%)

90/99 (91)108/114 (95)

Hazard ratio = 0.99(95% CI, 0.73 – 1.29)P value <0.001


7.4 (7.3-7.7)7.3 (6.4-7.9)


90

86

30

43

11

21

8

10

6

6

4

5

4

4

2

4

2

4

2

3

2

2

1

2

1

2

1

2

1

2

0

2

0

2

0

2

0

2

0

2

0

1

PFS in Patients With Mutant RAS* Exon mCRC

24

*Mutant in any KRAS or NRAS exon 2, 3, and 4

The role of EGFR inhibition in mCRC

• Anti EGFR MoAbs use is restricted to RAS wt mCRC

• They improve efficacy of chemotherapy on RR, PFS and OS in all randomized trials

• Compared to Bevacizumab in 1st line they improve – RR in 2/3 trials– PFS in 1/3 trial– OS in 2/3 trials (Full and matured data from CALGB are needed)– Meta-analysis favor the use of anti-EGFR 1st

• The sequence of targeted agent use seems important and should be studied in randomized trials.

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