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ESMO Preceptorship colorectal cancerSingapore 28-29th March 2015
Session VIThe role of EGFR inhibition in mCRC
JY DOUILLARD MD PhD
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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.
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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
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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
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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
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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)
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Impact of extended RAS analysis vs.KrasExon 2 on anti-EGFR MoAb efficacy in mCRC
Data from the PRIME trial
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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)
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PRIME: PFS by KRAS Mutation StatusWT KRAS MT KRAS
Eventsn (%)
Median (95% CI) months
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 (%)
Median (95% CI) months
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
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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
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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**
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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
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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
EXON 2 EXON 3 EXON 4EXON 1
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%
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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%‡
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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
Hazard ratio(P-value)
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;
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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 (%)
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)
WT RAS
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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)
Panitumumab + FOLFOX4 (n = 272) 187 (69) 15.6 (13.4–17.9)
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)
Panitumumab + FOLFOX4 (n = 51) 35 (69) 17.1 (10.8–19.4)
FOLFOX4 (n = 57) 33 (58) 18.3 (13.0–23.2)
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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
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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
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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
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Sorich MJ, et al. Ann Oncol. 2015;26:13-21.
Importance of Targeting the Right Population
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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
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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*
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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)
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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
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Additional points to consider for the use of anti-EGFR
Early tumor response (ETS)Duration of response (DoR)Deepness/Depth of Response DpR)
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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.
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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.
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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
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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)
Panitumumab + FOLFOX4
(n = 48)
FOLFOX4(n = 41)
Panitumumab + FOLFOX4
(n = 48)
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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
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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
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PEAK Study: PFS according to ETS
F Rivera ASCOGI 2015 Abst 660
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PEAK Study: Tumor Shrinkage with time
F Rivera ASCOGI 2015 Abst 660
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PEAK Study: Tumor Shrinkage impact on OS
F Rivera ASCOGI 2015 Abst 660
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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
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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
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Post-progression therapy
What is the impact of 2nd line on overall survival?Is there a preferred sequence of use for targeted agents?
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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
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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.
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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)
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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
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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
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The role of EGFR inhibition in mCRC
2nd and later lines data
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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
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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).
EXON 2 EXON 3 EXON 4EXON 1
12 13 61 117 146
EXON 2 EXON 3 EXON 4EXON 1
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
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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
HR = 0.70 (95% CI, 0.54–0.91)Log-rank p-value = 0.007
Months
WT RAS#,2
18
Eventsn (%)
Median, months (95% CI)
Panitumumab + FOLFIRI (n = 303)
178 (59) 5.9 (5.5–6.7)
FOLFIRI (n = 294) 203 (69) 3.9 (3.7–5.3)
Eventsn (%)
Median, months (95% CI)
Panitumumab + FOLFIRI (n = 208)
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
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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
HR = 0.85 (95% CI, 0.70–1.04)Log-rank p-value = 0.12
HR = 0.81 (95% CI, 0.63–1.03)Log-rank p-value = 0.08
Months Months
WT RAS2
2212 14 24 26 28 30 32
Eventsn (%)
Median, months (95% CI)
Panitumumab + FOLFIRI (n = 208)
130 (63) 16.2 (14.5–19.7)
FOLFIRI (n = 213) 143 (67) 13.9 (11.9–16.0)
Eventsn (%)
Median, months (95% CI)
Panitumumab + FOLFIRI (n = 303)
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
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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
Hazard ratio(P-value)
0.73(P = 0.004)
0.695(P = 0.006)
Median OS, months
14.5 12.5 16.2 13.9
Hazard ratio(P-value)
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)
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PANITUMUMAB single agenttreatment of metastatic colorectal cancer
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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
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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%
EXON 2 EXON 3 EXON 4EXON 1
NRAS12 13 61 117 146
1%3%4%
18% additional mutations
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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%
0 844 12 60WeeksPatients at risk
73
63
Panitumumab + BSC (n=73)BSC alone (n = 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
Median weeks(95 % CI)
14.1 (10.3-23.3)7.3 (6.0-7.4)
Panitumumab+ BSCBSC alone
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%
0 844 12 60WeeksPatients at risk
99
114
Panitumumab + BSC (n=99)BSC alone (n = 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
Median weeks(95 % CI)
7.4 (7.3-7.7)7.3 (6.4-7.9)
Panitumumab+ BSCBSC alone
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
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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.