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 (%)
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
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
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%
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
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;
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
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)
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)
Panitumumab + FOLFOX4
(n = 48)
FOLFOX4(n = 41)
Panitumumab + FOLFOX4
(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
F Rivera ASCOGI 2015 Abst 660
PEAK Study: Tumor Shrinkage impact on OS
F Rivera ASCOGI 2015 Abst 660
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
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.
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).
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
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
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
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)
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%
EXON 2 EXON 3 EXON 4EXON 1
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%
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
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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