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
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Identification of potentially responsive subsets when cetuximab is added to oxaliplatin-fluoropyrimidine chemotherapy (CT) in first line advanced colorectal.
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
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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
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 capoxaliplatin
FU or capoxaliplatin
FU or capoxaliplatin
Arm C
INTERMITTENT CT Treat for 12 weeks then stop and monitor. Restart on progression for a further 12 weeks
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 BN randomised 815 815 367 362 268 297Overall 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=1.08
P=0.428OR=1.35P=0.049
OR=0.88P=0.449
Significant reduction in 2nd-line treatment in the Cetuximab arm
62%
50%56%
44%
010
2030
4050
6070
% o
f elig
ible
pat
ient
s
Any Irinotecan
65%
53%54%
42%
Any IrinotecanP=0.015 P=0.032
Arm AArm 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
MaleFemale
<=65y>65y
0/12+
Xelox
OxMdG
581
408173
338243
230351
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 XELOXIn Control Arm (A) Higher toxicity
Neutropenia, stomatitis
Higher dose intensity
In combination arm (B)
Maintained oxaliplatin dose
intensity
Higher GI toxicityProtocol reduction of
capecitabine doseReduced 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 PopeMedical Genetics Cardiff Jeremy Cheadle, Chris Smith, Bharat
Jasani, Michelle James, Shelley Idziaszczyk, Wales Cancer Bank Alison Parry-JonesLeuven Dieter Lambrechts