Background

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


1700mg/m2/dayd1-14, q21 x4

CRT (50.4Gy/28#)

withCapecitabine

1650mg/m2/day


1700mg/m2/dayd1-14, q21 x4


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


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



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


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%)


MRI defined high risk factors


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


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)


PFS - wild type


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


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


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


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


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


* 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


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

Documents

Background