EXPERT-C: A randomized phase II European multicenter trial of neoadjuvant chemotherapy
(capecitabine/oxaliplatin) and chemoradiation (CRT) with or without cetuximab followed by total
mesorectal excision (TME) in patients with MRI-defined high-risk
Dewdney A, Capdevila J, Glimelius B, Cervantes A, Tait D, Brown G, Wotherspoon A, Gonzalez de Castro D, Chua YJ, Wong R, Barbachano Y, Oates J, Chau I and Cunningham D
Background• Circumferential resection margin (CRM) involvement results in higher rates of local recurrence and poorer survival1
• High resolution MRI can accurately stage rectal cancer and predict potential CRM involvement2
• Short course pre op radiotherapy3 & chemoradiation4 (CRT) both reduce local recurrence rates but do not consistently impact overall survival
1Nagtegaal et al JCO 2008 2MERCURY Study Group BMJ 2006 , 3 Swedish Rectal Cancer Trial
NEJM 1997 4Bosset et al NEJM 2006 GI Clinical Trials Unit
Background
1Chua et al Lancet Oncol 2010 GI Clinical Trials Unit
• The rationale for neoadjuvant chemotherapy includes downstaging the primary tumour and the reduction of distant recurrence
• EXPERT1 – a single arm phase II trial (n=105) of oxaliplatin and capecitabine before CRT and TME in MRI-defined poor-risk rectal cancer
- response to neoadjuvant chemotherapy 74%
- response to CRT 89%
- pCR 20%
- 5 year PFS 64% & 5 year OS 75%
Rationale for Cetuximab• Response - in mCRC improves RR and PFS in
irinotecan refractory patients1 and in combination with FOLFIRI2
• Radiosensitisation - combined with radical radiotherapy in H&N cancers improves local control and OS3
• Toxicity - in rectal cancer phase I/II trials with CRT no unexpected toxicity4
1Cunningham et al NEJM 2004, 2Van Cutsem et al NEJM 2009,3Bonner et al NEJM 2006, 4Glynne Jones et al Acta Oncol 2010
GI Clinical Trials Unit
EXPERT-C trial design
R
Oxaliplatin 130mg/m2 d1Capecitabine
1700mg/m2/dayd1-14, q21 x4
CAPOXN=81
CAPOX + CN=84
CRT (50.4Gy/28#)
withCapecitabine
1650mg/m2/day
TME
TME
15 European centres
Oxaliplatin 130mg/m2 d1Capecitabine
1700mg/m2/dayd1-14, q21 x4
CRT (50.4Gy/28#)
withCapecitabine
1650mg/m2/day
Oxaliplatin 130mg/m2 d1Capecitabine
1700mg/m2/dayd1-14, q21 x4
Oxaliplatin 130mg/m2 d1Capecitabine
1700mg/m2/dayd1-14, q21 x4
0 3 6 9 12 18 0 3 6 9 12
Cetuximab 400mg/m2 loading dose followed by 250mg/m2 week
Weeks
Inclusion criteria• Histological diagnosis of operable rectal
adenocarcinoma • No evidence of metastatic disease• MRI defined high risk, at least one of the following;
≤1mm of mesorectal fascia (involved CRM)
Extension ≥5mm into peri-rectal fat
T4
Extramural venous invasion
T3 at/below levators
GI Clinical Trials Unit
Study objectives• Primary endpoint:
Complete response; pCR or radiological complete response (in those who did not undergo surgery) in patients with KRAS & BRAF wild type tumours
• Secondary endpoints:
Radiological response rate, PFS, OS, Safety & QoL• Translational analysis:
KRAS, BRAF, PIK3CA & NRAS mutations
PTEN loss
EGFR gene copy numberGI Clinical Trials Unit
Statistical designOriginal trial design
• 82 patients each arm• Detect 20% difference in pCR• Power = 80% • 2 sided Alpha =0.05
Protocol modified to analyse wild type population• ~60% of patients KRAS/BRAF wild type• 50 wild type patients in each arm• Odds ratio of 3.4
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GI Clinical Trials Unit
164 patients
149 patients
90 wild type(60%)
CAPOXn=44
CAPOX + Cn=46
59 mutant(40%)
CAPOXn=32
CAPOX + Cn=27
Insufficient material n=15 (pCR n=8)
Wild Type population
Biomarker Number %
KRAS/BRAF wild type 90/149 60
KRAS mutation 56/149 38
Codon 12 43/56 78
Codon 13 10/56 18
Codon 61 2/56 4
BRAF mutation 3/149 2
PIK3CA mutation 10/143 7
EXON 9 5/10 50
EXON 20 5/10 50
NRAS mutation 4/140 3
PTEN loss 19/149 13
↑EGFR gene copy number 14/139 10
Amplification 2/14 14
Polysomy 12/14 86
Translational analysis- All treated population
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Patient characteristics
CAPOX CAPOX + C
All treated(n=81)
Wild type(n=44)
All treated(n=83)
Wild type(n=46)
Sex
Male 47 (58%) 23 (52%) 54 (65%) 31(67%)
Female 34 (42%) 21 (48%) 29 (35%) 15 (33%)
Median age(range)
65 (28-79)
63(28-79)
61(31-75)
58(31-75)
WHO PS
0 39 (48%) 22 (50%) 39 (47%) 23 (50%)
1 41 (51%) 22 (50%) 42 (51%) 21 (46%)
2 1 (1%) 0 2 (2%) 2 (4%)
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MRI defined high risk factors
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CAPOX CAPOX + C
All treated(n=81)
Wild type(n=44)
All treated(n=83)
Wild type(n=46)
T3c-T3d 56 (69%) 33 (75%) 47 (57%) 23 (50%)
T4 19 (23%) 11 (25%) 21 (25%) 12 (26%)
CRM involved/at risk 45 (56%) 25 (57%) 48 (58%) 26 (57%)
EMVI positive 60 (74%) 33 (75%) 58 (70%) 33 (72%)
Low lying tumour (at/ below levators)
38 (47%) 20 (45%) 39 (47%) 22 (48%)
Radiological response – wild typeNeoadjuvant chemotherapy Neoadjuvant chemotherapy
and Chemoradiation
CAPOX CAPOX + C CAPOX CAPOX + C
CR 1 (2%) 5 (11%) 2 (4%) 7 (15%)
PR 21 (48%) 27(59%) 30 (68%) 34 (74%)
SD 20 (45%) 12 (26%) 6 (14%) 3 (7%)
PD 1 (2%) 0 4 (9%) 0
Overall response
22 (50%) 32 (70%) 32 (72%) 41 (89%)
p=0.038 p=0.028
Surgical outcome
No statistical difference in rates of R0 resection, sphincter sparing surgery or surgical complications
CAPOX CAPOX + C
All treated
n=81
Wild Type
n=44
All treated
n=83
Wild Type
n=46
Underwent surgery
74 (91%) 41 (93%) 78 (94%) 45 (98%)
Operable 72 (88%) 40 (91%) 77 (93%) 45 (98%)
R0 resection 66 (82%) 37 (84%) 74 (89%) 43 (93%)
R1 resection 4 (4%) 3 (7%) 1 (1%) 0
R2 resection 2 (2%) 1 (2%) 2 (2%) 2 (5%)
APR 22 (27%) 11 (25%) 23 (27%) 13 (28%)
Peri-op death 2 (2%) 1 (2%) 0 0
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Primary endpoint- wild type
Results
CAPOX
n= 44
CAPOX + C
n=46
Significance
CR 4 (9%) 5 (11%) p= 1.0
pCR 3 (7%) 5 (11%) p= 0.714
Odds radio= 1.0
CR = pCR and complete radiological response (in those who did not have surgery)
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PFS - wild type
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CAPOX + C CAPOX
HR = 0.81; 95% CI (0.3-2.16) p= 0.668 3 yr PFS CAPOX 81% vs CAPOX + C 80%
CAPOX + C CAPOX
Overall survival -wild type
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CAPOX + C CAPOX
HR= 0.27; 95% CI (0.07-0.99) p=0.0353 yr OS CAPOX 81% vs CAPOX + C 96%
Relapse rates- wild types
CAPOX CAPOX + C
On/within 6 months of treatment
≥ 6 months after completion of treatment
On/within 6 months of treatment
≥ 6 months after completion of treatment
Overall recurrence rate
9 (18%) 1(2%) 1 (2%) 7 (15%)
Local progession/ recurrence only
1 (2%) 0 0 1 (2%)
Distant recurrence only
7 (16%) 1 (2%) 1 (2%) 6 (13%)
Local & distant progession/ recurrence
1 (2%) 0 0 0
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All treated population
Endpoint CAPOX CAPOX + C Significance
RR chemo 40 (50%) 49 (59%) p= 0.41
RR CRT 57 (69%) 64 (77%) p= 0.23
CR 12 (15%) 15 (18%) p = 0.574.
pCR 11 (14%) 15 (18%) p= 0.453
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3 yr PFS 70% vs 71% p=0.614
CAPOX + CCAPOX
CAPOX + CCAPOX
3 yr OS 78 vs 86% p=0.077
Number at risk
Overall survivalWild type population All treated population
Mutant population Wild type + KRAS Codon 13
CAPOXCAPOX + C
CAPOX +CCAPOX
CAPOX + CCAPOX
CAPOX + CCAPOX
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CAPOX + CCAPOX
CAPOX + CCAPOX
p= 0.077
p= 0.0107
p= 0.035
p= 0.579
Grade ≥3 toxicityNeoadjuvant
chemotherapyChemoradiation Adjuvant
chemotherapyCAPOX
n=81
CAPOX + C
n=83
Cap
n=75
Cap + C
n=78
CAPOX
n=52
CAPOX + C
n=65
Febrile neutropenia
1* 1* 0 0 0 0
Diarrhoea 9 8 1 10 6 16
Stomatitis 0 1 0 1 0 2
PPE 1 4 1 4 0 3
Skin rash 0 10 0 9 2 10
Neuropathy 0 2 0 0 10 5
Thrombosis 1 0 1 0 4 3
Death 1 1 0 0 0 0
% Patients commencing and completing treatment
Commenced 100 100 93 94 64 78
Completed 93 95 90 91 63 67
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* Grade 5
Translational analysis
KRAS wild type
93
BRAF Mutant
2
KRAS mutant 56
PIK3CA mutation
7
1
↑EGFR GCN
2
84
*Number of patients with molecular event
NRAS Mutant
3Loss PTEN
1
18
18
Univariate analysis
• None of the biomarkers tested predicted for CR• In univariate analysis of the all treated population KRAS
mutation predicted for worse PFS and OS and PTEN loss predicted for worse OS.
• Only KRAS mutation remained significant for worse PFS and OS on multivariate analysis (all treated)
Biomarker
PFS OS
All treated Wild type All treated Wild type
KRAS mutation yes n/a yes n/a
BRAF mutation no no no no
PIK3CA mutation no no no no
NRAS mutation no no no no
PTEN loss no no yes no
↑EGFR GCN no no no no
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Conclusions• In the wild type population, addition of cetuximab resulted in:
Significant improvement in radiological response to neoadjuvant chemotherapy (50% vs. 72%, p=0.038) and CRT (72% vs. 89%, p=0.028)
No difference in CR (9% vs 11%) and pCR (7% vs 11%) Significant improvement in 3 year overall survival (81%
vs. 96% p=0.035)
• 8/26 of patients achieving a pCR had insufficient tissue for molecular analysis, 6 of whom received cetuximab
• Skin toxicity was more frequent with cetuximab during neoadjuvant chemotherapy and CRT, but diarrhoea was only significantly increased during CRT