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Identification of potentially responsive subsets when cetuximab is added to oxaliplatin-fluoropyrimidine chemotherapy (CT) in first line advanced colorectal cancer (aCRC): mature results of the MRC COIN trial - PowerPoint PPT Presentation
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Identification of potentially responsive subsets when cetuximab is added to
oxaliplatin-fluoropyrimidine chemotherapy (CT) in first line
advanced colorectal cancer (aCRC): mature results of the MRC COIN trial Maughan TS, Adams RA, Smith C, Seymour M, Wilson R, Meade A,
Fisher D, Madi A, Cheadle J, Kaplan R
on behalf of the MRC COIN Trial Investigators
NCRI Colorectal Clinical Studies Group
COIN Trial design
OxMdG: 2 weekly IV l-folinic acid 175 mg, oxaliplatin 85mg/m2 over 2 h, IV bolus 5-FU 400mg/m2, 5-FU 2400mg/m2 inf. 46 h via ambulatory pump (mFOLFOX)
XELOX: 3 weekly IV oxaliplatin 130mg/m2 over 2 h, capecitabine 1000mg/m2 p.o. bd for 2 weeks (reduced to 850 mg/m2 in Arm B from July 07 for toxicity)
Pts/clinicians chose OxMdG or XELOX before randomisation.
5FU or capecitabineoxaliplatin
Arm A
CONTINUOUS CT until progression, toxicity or patient choice
5FU or capecitabineoxaliplatincetuximab
Arm B
CONTINUOUS CT until progression, toxicity or patient choice
FU or cap
oxaliplatin
FU or cap
oxaliplatin
FU or cap
oxaliplatinArm C
INTERMITTENT CT Treat for 12 weeks then stop and monitor. Restart on progression for a further 12 weeks
Second Line
Chemo-therapy
IrinotecanBased
815
815
815
InclusionAdvanced colorectal
cancer, First line therapy,
No prior chemo for metastatic disease,
No prior EGFR IHC
PS0-2,
Good organ function
COIN question 2Is intermittent CT non-inferior?Adams poster discussion Tuesday abstract #3525
COIN question 1
• Does the addition of cetuximab to oxaliplatin based chemotherapy improve overall survival?
• Primary endpoint: Overall Survival• In patients with no mutation detected in codons 12,13
and 61 of KRAS
• Secondary endpoints• Overall survival in KRAS mutant, ‘all’ wildtype (KRAS, NRAS,
BRAF), ‘any’ mutant, ITT• Progression Free Survival • Response• Quality of Life (including Dermatology Life Quality Index)• Health economic evaluation
Baseline Characteristics
All pts KRASwt
Total randomised 2,445 1,123
Choice of chemo at baseline
Xelox 66% 66%
OxMdG 34% 34%
SexMale 65% 68%
Female 35% 32%
Agemedian 63 64
≥75 yrs 9% 8%
WHO PS
0 46% 47%
1 46% 47%
2 8% 6%
Prior adjuvant chemotherapy
None 75% 73%
1-6mo 4% 4%
>6mo 16% 18%
Yes, unspecified 5% 5%
Presented for entire trial population, no significant differences were identified between arms
All pts KRASwt
Total randomised 2,445 1,123
Site of primary Rectum 31% 31%
Status of primary tumour
Resected 53% 54%
Unresected 42% 39%
Local recurrence 5% 7%
Metastases
Metachronous 30% 32%
Synchronous 69% 67%
Liver only 22% 24%
Liver + others 53% 51%
Non-liver 24% 24%
No. of metastatic sites
1 36% 37%
2 40% 40%
> 2 24% 22%
Mutations in Kras, Nras and Braf: distribution and prognostic significance
BRAF mutation All patientsAny mutationKRAS mutation
KRAS wild-typeAll wild-type
Mutation status:
06
12
Med
ian
PFS
(m
on
ths) Arm A Arm B
06
12
18
Med
ian
OS
(m
on
ths)
57340
268815
367289
45366
297815
362292
01
02
03
04
0
2-y
ear
OS
(%
)
N:
Prognostic effect of mutational status
“All-wt”n=581 (44%)
KRAS-mutn=565 (43%)
NRAS-mutn=50 (4%)
BRAF-mutn=102 (8%)
Totaln=1316 (81%)
554
11
39
102
Population N Arm A Arm B
ITT 1630 815 815
Assessed for mutations
1316 648 668
of which:- KRAS mutation- NRAS mutation- BRAF mutation
565 (43%)50 (4%)
102 (8%)
2681857
2973245
KRAS wt 729 (55%)
367 362
KRAS/NRAS/BRAF-wt“All wild-type”
581 (44%)
289 292
Grade 3-5 Toxicities and deaths
Neutrophils WBC
HbPlatelets Arm A
Arm B
* = p<0.05** = p<0.01
*** = p<0.001
N patients experiencing at least one CTC Grade 3+ toxicity whilst receiving COIN protocol therapy
0 50 100 150 200
***
Hand-foot Skin rash
Nail changes ***
***
***
Neuropathy **
Diarrhoea Vomiting
Nausea
***
Stomatitis ***
Anorexialow Mg ***
**
Others
Lethargy ***
**
All pts KRASwt
Arm A Arm B Arm A Arm B
Randomised 815 815 367 362
Deaths < 60 days of randomisat’n
4.4% 5.3% 4.1% 4.4%
Safety population
(started allocated treatment)
791
97%
802
98%
358
98%
357
99%
All deaths ≤30 days of start of last trt. cycle
6.1% 7.7% 5.6% 7.0%
Treatm’t-rel. deaths ≤30 days of start of last trt. cycle
1.3% 1.1% 1.4% 0.8%
Arm A Arm B Diff.
Median OS : mo 17.9 17.0 -0.92
2-year survival rates 36.1% 34.4% -1.66%
Arm A
Arm B Diff.
Median PFS: mo 8.6 8.6 +0.07
2-year survival rates 8.83% 9.55% +0.72%
OS (primary analysis) and PFS among KRAS wild-type patients
0.00
0.25
0.50
0.75
1.00
Sur
viva
l
362 306 238 149 80 42 17 3 B
367 316 250 154 83 44 19 1A
N patients at risk:
0 6 12 18 24 30 36 42Time (months)
Arm A (OxFp)
Arm B (OxFp + cetux)
HR point estimate = 1.03895% CI = (0.90, 1.20)Χ2 = 0.18; p = 0.68
Overall Survival Progression-free Survival
361 249 103 42 22 9 6 0
367 245 92 41 18 11 6 1
0 6 12 18 24 30 36 42Time (months)
HR point estimate = 0.95995% CI = (0.84, 1.09)Χ2 = 0.27; p = 0.60
Arm A (OxFp)
Arm B (OxFp + cetux)
Overall Survival:by mutation status: KRAS, NRAS, BRAF
Arm A Arm B Diff.
Median survival:(mo) 20.1 19.9 -0.20
2-year survival rates
40.0% 38.8%
-1.24%
292 258 211 136 70 37 15 3B
289 256 208 133 76 41 19 1A
N patients at risk:
366 290 187 108 65 27 13 0
340 285 198 108 46 19 7 1
Arm A Arm B Diff.
Median survival: (mo) 14.4 12.7 -1.64
2-year survival rates 21.2% 25.5%
+4.29%
All wild type Any mutation
0.00
0.25
0.50
0.75
1.00
Sur
viva
l
0 6 12 18 24 30 36 42Time (months)
Arm A (OxFp)
Arm B (OxFp + cetux)
HR point estimate = 1.01995% CI = (0.86, 1.20)Χ2 = 0.03; p = 0.86
0 6 12 18 24 30 36 42Time (months)
Arm A (OxFp)
Arm B (OxFp + cetux)
HR point estimate = 1.00495% CI = (0.87, 1.15)Χ2 = 0.00; p = 0.96
Progression Free Survival:by mutation status: KRAS, NRAS, BRAF
366 200 59 21 8 4 2 0
340 204 61 24 7 2 1 0
Time (months)
Arm A
Arm B Diff.
Median PFS: mo 8.8 9.2
+0.43
2-year PFS rates10.2
%10.8
%+0.55
%
Arm A
Arm B Diff.
Median PFS: mo 6.6 6.3 -0.33
2-year PFS rates3.45
%3.19
% -0.26%
All wild-type Any mutation
0.00
0.25
0.50
0.75
1.00
Sur
viva
l
292 220 94 37 19 8 5 0Arm B
289 200 75 35 18 11 6 1Arm A
No at risk
0 6 12 18 24 30 36 42
Time (months)
Arm A (OxFp)
Arm B (OxFp + cetux)
HR = 0.92295% CI = (0.80, 1.07)97% CI = (0.78, 1.09)
p = 0.36
0 6 12 18 24 30 36 42
Arm A (OxFp)
Arm B (OxFp + cetux)
HR = 1.07995% CI = (0.95, 1.23)97% CI = (0.93, 1.25)
p = 0.33
Response
Improved response rate in KRAS wt overall and at 12 weeks
All responses are investigator assessed, with no confirmatory scans
All pts KRASwt KRASmut
Arm A Arm B Arm A Arm B Arm A Arm B
N randomised 815 815 367 362 268 297
Overall Response Rate at 12 weeks
45% 49% 50% 59% 41% 40%
Odds ratio (B vs A) OR=1.17P=0.124
OR=1.44P=0.015
OR=0.97P=0.877
Best Overall Response(CR/PR at any time) 51% 53% 57% 64% 46% 43%
Odds ratio (B vs A) OR=1.08P=0.428
OR=1.35P=0.049
OR=0.88P=0.449
Significant reduction in 2nd-line treatment in the Cetuximab arm
62%
50%
56%
44%
01
02
03
04
05
06
07
0
% o
f elig
ible
pati
ents
Any Irinotecan
65%
53%54%
42%
Any Irinotecan
P=0.015 P=0.032
Arm A
Arm B
P=0.006 P=0.008
All patients KRASwt patients
Second line therapy received
0.88 (0.72, 1.08)
1.05 (0.75, 1.46)
428
153
<10,000/l
≥10,000/l
All pts
Sex
Age
Met sites
Fp therapy
Subgroup
Male
Female
<=65y
>65y
0/1
2+
Xelox
OxMdG
581
408
173
338
243
230
351
391
190
N
0.92 (0.78, 1.10)
0.87 (0.71, 1.07)
1.02 (0.74, 1.41)
1.00 (0.80, 1.26)
0.81 (0.62, 1.06)
0.73 (0.55, 0.97)
1.07 (0.86, 1.33)
1.02 (0.82, 1.26)
0.72 (0.53, 0.98)
HR (95% CI)
Favours cetuximab Favours no cetuximab
10.25 0.5 2 4
Interactionp-value
P=0.381
P=0.222
P=0.036
P=0.103
Predefined Subgroup analysesTo maximise responsiveness, sample used was “all wild-type” and outcome was PFS.
WBCP=0.411
Forest plot (PFS): kras status; choice of Fp; no of metastatic sites
KRAS-wt
KRAS-wt
KRAS-wt
KRAS-wt
KRAS-wt
KRAS-mut
KRAS-mut
KRAS-mut
KRAS-mut
KRAS-mut
Mutational status
OxMdG
Xelox
OxMdG
Xelox
OxMdG
Xelox
OxMdG
Xelox
OxFp therapy
0/1
0/1
2+
2+
0/1
0/1
2+
2+
N metastatic sites at baseline
729
96
184
148
301
565
63
135
116
251
N
0.96 (0.82, 1.12)
0.55 (0.35, 0.87)
1.02 (0.75, 1.40)
1.03 (0.73, 1.44)
1.05 (0.83, 1.33)
1.07 (0.90, 1.26)
0.96 (0.57, 1.61)
0.86 (0.60, 1.23)
1.06 (0.73, 1.54)
1.25 (0.96, 1.61)
HR (95% CI)
0.55 (0.35, 0.87)
10.33 0.5 2
All All
All All
Favours cetuximab Favours no cetuximab
Increased GI toxicity led toCapecitabine dose reduction
Capecitabine dose was reduced in arm B from 1000 to 850 mg/m2 b.d. because of increased Gastrointestinal toxicity
Xelox:
OxMdG
% of all randomised pts reporting diarrhoea G3+at any time whilst on trial
P-values
vs OxMdG,Arm B
B vs A
P=0.00520%11%
P=0.030P<0.00126%15%All
P=0.002P<0.00130%17%Before dose reduction
P=0.41P=0.2516%12%After dose reduction
279
536 534
Arm A Arm Bn n
281
153
381
Differentiating infusional 5FU/FA (OxMdG) and capecitabine (XELOX)
OxMdG XELOX
In Control Arm (A) Higher toxicityNeutropenia,
stomatitis
Higher dose intensity
In combination arm (B)
Maintained oxaliplatin dose
intensity
Higher GI toxicityProtocol reduction of
capecitabine dose
Reduced DI
Duration of therapy No differences with addition of cetuximab
Second line therapy Significantly lower usage of second
line therapy
Trend to reduction in second line
therapy
Summary
• Largest trial of EGFR targeted treatment in first-line ACRC setting• Prospective overall survival analysis by KRAS status
• >80% patients genotyped for KRAS, NRAS and BRAF• 43% KRAS mutation; 4% NRAS mutation; 8% BRAF mutation
• The addition of cetuximab to oxaliplatin based chemotherapy is associated with:
• For all patients• Increased non-haematological toxicity• No change in OS or PFS
• For KRASwt patients• Increased non-haematological toxicity• No change in OS (primary endpoint) or PFS• Increased response rate
Conclusions
• In this negative study, subgroup analyses suggest that there may be a benefit for cetuximab in combination with oxaliplatin chemotherapy in patients with• KRAS wildtype tumours, • Limited metastatic disease (0/1 metastatic sites), • Used in combination with infusional 5FU and oxaliplatin
• The differential benefit for choice of fluoropyrimidine and distribution of disease requires validation from other datasets
• Strong prognostic effect of KRAS, BRAF and NRAS mutation status independent of the use of cetuximab
Thank you
2445 Patients and families for agreeing to enter the trial
• PIs/clinicians• Research nurses• Research networks
• NCRN• WCTN• SCRN• NICRN• ICORG
• Cancer Research-UK• MRC• Merck-Serono• NHS R&D• Cancer Research Wales• Cardiff University• NCRI
MRC CTUTrial Managers Sarah Kenny, Ed KayStatisticians David Fisher, Lindsay ThompsonData Managers Jenna Mitchell, Laura Nichols, Cheryl
Courtney, Louise Clement, Ben SydesSenior staff Angela Meade, Rick Kaplan, Max Parmar
Lynda Harper
Trial Management GroupCo-applicants Matt Seymour, Richard Wilson, Jim CassidyTrial Fellows Richard Adams, Ayman MadiPharmacy, Nurse Elizabeth Hodgkinson, Penny RogersQL, HE Richard Stephens, Mark SculpherPatient Malcolm Pope
Medical Genetics Cardiff Jeremy Cheadle, Chris Smith, Bharat
Jasani, Michelle James, Shelley Idziaszczyk, Wales Cancer Bank Alison Parry-JonesLeuven Dieter Lambrechts