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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.

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Background

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  1. 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

  2. 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 19974Bosset et al NEJM 2006 GI Clinical Trials Unit

  3. Background • 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% 1Chua et al Lancet Oncol 2010 GI Clinical Trials Unit

  4. 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

  5. EXPERT-C trial design Oxaliplatin 130mg/m2 d1 Capecitabine 1700mg/m2/day d1-14, q21 x4 CRT (50.4Gy/28#) with Capecitabine 1650mg/m2/day TME Oxaliplatin 130mg/m2 d1 Capecitabine 1700mg/m2/day d1-14, q21 x4 CAPOX N=81 R 15 European centres Oxaliplatin 130mg/m2 d1 Capecitabine 1700mg/m2/day d1-14, q21 x4 CRT (50.4Gy/28#) with Capecitabine 1650mg/m2/day TME Oxaliplatin 130mg/m2 d1 Capecitabine 1700mg/m2/day d1-14, q21 x4 CAPOX + C N=84 Weeks 0 3 6 9 12 18 0 3 6 9 12 Cetuximab 400mg/m2 loading dose followed by 250mg/m2 week

  6. 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

  7. 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 number GI Clinical Trials Unit

  8. Statistical design Original 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 GI Clinical Trials Unit

  9. Wild Type population 164 patients Insufficient material n=15 (pCR n=8) 149 patients 90 wild type (60%) 59 mutant (40%) CAPOX n=44 CAPOX + C n=46 CAPOX n=32 CAPOX + C n=27 GI Clinical Trials Unit

  10. Translational analysis- All treated population GI Clinical Trials Unit

  11. Patient characteristics GI Clinical Trials Unit

  12. MRI defined high risk factors GI Clinical Trials Unit

  13. Radiological response – wild type

  14. Surgical outcome • No statistical difference in rates of R0 resection, sphincter sparing surgery or surgical complications GI Clinical Trials Unit

  15. Primary endpoint- wild type Odds radio= 1.0 CR = pCR and complete radiological response (in those who did not have surgery) GI Clinical Trials Unit

  16. 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 GI Clinical Trials Unit

  17. Overall survival -wild type CAPOX + C CAPOX HR= 0.27; 95% CI (0.07-0.99) p=0.035 3 yr OS CAPOX 81% vs CAPOX + C 96% GI Clinical Trials Unit

  18. Relapse rates- wild types GI Clinical Trials Unit

  19. All treated population CAPOX + C CAPOX CAPOX + C CAPOX 3 yr PFS 70% vs 71% p=0.614 3 yr OS 78 vs 86% p=0.077 Number at risk GI Clinical Trials Unit

  20. Overall survival Wild type population All treated population CAPOX + C CAPOX p= 0.077 CAPOX + C CAPOX p= 0.035 CAPOX +C CAPOX Mutant population Wild type + KRAS Codon 13 CAPOX + C CAPOX CAPOX + C CAPOX p= 0.0107 p= 0.579 CAPOX CAPOX + C GI Clinical Trials Unit

  21. Grade ≥3 toxicity * Grade 5 GI Clinical Trials Unit

  22. Translational analysis KRAS wild type 93 PIK3CA mutation BRAF Mutant 2 KRAS mutant 56 1 7 2 ↑EGFR GCN 4 8 NRAS Mutant 3 Loss PTEN 1 1 8 8 1 *Number of patients with molecular event

  23. 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)

  24. 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 GI Clinical Trials Unit

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