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COIN Trial design

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

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COIN Trial design

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  1. 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

  2. COIN Trial design Inclusion Advanced colorectal cancer, First line therapy, No prior chemo for metastatic disease, No prior EGFR IHC PS0-2, Good organ function Second Line Chemo- therapy Irinotecan Based Arm A 815 FU or cap 5FU or capecitabine 5FU or capecitabine FU or cap FU or cap CONTINUOUS CT until progression, toxicity or patient choice oxaliplatin oxaliplatin oxaliplatin oxaliplatin oxaliplatin Arm B 815 cetuximab CONTINUOUS CT until progression, toxicity or patient choice COIN question 2Is intermittent CT non-inferior? Adams poster discussion Tuesday abstract #3525 Arm C 815 INTERMITTENT CTTreat for 12 weeks then stop and monitor. Restart on progression for a further 12 weeks 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.

  3. 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

  4. Baseline Characteristics Presented for entire trial population, no significant differences were identified between arms

  5. Mutations in Kras, Nras and Braf: distribution and prognostic significance Prognostic effect of mutational status NRAS-mut n=50 (4%) KRAS-mut n=565 (43%) Arm A Arm B 12 “All-wt” n=581 (44%) BRAF-mut n=102 (8%) Median PFS (months) 6 39 0 11 18 102 554 12 Total n=1316 (81%) Median OS (months) 6 0 40 30 2-year OS (%) 20 10 0 297 362 57 268 367 45 N: 340 815 289 366 815 292 Mutation status: BRAF mutation All patients Any mutation KRAS wild-type KRAS mutation All wild-type

  6. Grade 3-5 Toxicities and deaths Platelets Arm A Hb *** Arm B WBC * = p<0.05 ** = p<0.01 *** = p<0.001 Neutrophils Nail changes *** *** Skin rash *** Hand-foot Nausea Vomiting Diarrhoea *** ** Neuropathy low Mg *** ** Anorexia *** Stomatitis *** Lethargy ** Others 0 50 100 150 200 N patients experiencing at least one CTC Grade 3+ toxicity whilst receiving COIN protocol therapy

  7. OS (primary analysis) and PFS among KRAS wild-type patients Overall Survival Progression-free Survival 1.00 HR point estimate = 1.038 95% CI = (0.90, 1.20) Χ2 = 0.18; p = 0.68 HR point estimate = 0.959 95% CI = (0.84, 1.09) Χ2 = 0.27; p = 0.60 0.75 0.50 Survival 0.25 Arm A (OxFp) Arm A (OxFp) Arm B (OxFp + cetux) Arm B (OxFp + cetux) 0.00 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 Time (months) Time (months) N patients at risk: 367 245 92 41 18 11 6 1 A 367 316 250 154 83 44 19 1 361 249 103 42 22 9 6 0 362 306 238 149 80 42 17 3 B

  8. Overall Survival:by mutation status: KRAS, NRAS, BRAF Any mutation All wild type 1.00 HR point estimate = 1.004 95% CI = (0.87, 1.15) Χ2 = 0.00; p = 0.96 HR point estimate = 1.019 95% CI = (0.86, 1.20) Χ2 = 0.03; p = 0.86 0.75 0.50 Survival 0.25 Arm A (OxFp) Arm A (OxFp) Arm B (OxFp + cetux) Arm B (OxFp + cetux) 0.00 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 Time (months) Time (months) N patients at risk: 1 46 19 7 340 285 198 108 256 1 289 208 133 76 41 19 A 0 65 27 13 366 290 187 108 292 B 258 3 211 136 70 37 15

  9. Progression Free Survival:by mutation status: KRAS, NRAS, BRAF All wild-type Any mutation 1.00 0.75 HR = 1.079 95% CI = (0.95, 1.23) 97% CI = (0.93, 1.25) p = 0.33 HR = 0.922 95% CI = (0.80, 1.07) 97% CI = (0.78, 1.09) p = 0.36 0.50 Survival Arm A (OxFp) Arm A (OxFp) Arm B (OxFp + cetux) Arm B (OxFp + cetux) 0.25 0.00 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 Time (months) Time (months) No at risk Arm A 340 204 61 24 7 2 1 0 289 200 75 35 18 11 6 1 366 200 59 21 8 4 2 0 292 220 94 19 8 5 0 Arm B 37

  10. Response • Improved response rate in KRAS wt overall and at 12 weeks • All responses are investigator assessed, with no confirmatory scans

  11. Second line therapy received KRASwt patients All patients 70 65% 62% Arm A 60 56% 54% Arm B 53% 50% 50 44% 42% 40 % of eligible patients 30 20 10 0 P=0.015 P=0.032 P=0.006 P=0.008 Any Irinotecan Any Irinotecan Significant reduction in 2nd-line treatment in the Cetuximab arm

  12. Predefined Subgroup analyses To maximise responsiveness, sample used was “all wild-type” and outcome was PFS. Interaction p-value Subgroup N HR (95% CI) All pts 581 0.92 (0.78, 1.10) Sex Male 408 0.87 (0.71, 1.07) P=0.381 Female 173 1.02 (0.74, 1.41) Age <=65y 338 1.00 (0.80, 1.26) P=0.222 >65y 243 0.81 (0.62, 1.06) Met sites 0/1 230 0.73 (0.55, 0.97) P=0.036 2+ 351 1.07 (0.86, 1.33) Fp therapy Xelox 391 1.02 (0.82, 1.26) P=0.103 OxMdG 190 0.72 (0.53, 0.98) WBC <10,000/l 428 0.88 (0.72, 1.08) P=0.411 ≥10,000/l 153 1.05 (0.75, 1.46) 0.25 0.5 1 2 4 Favours cetuximab Favours no cetuximab

  13. Forest plot (PFS): kras status; choice of Fp; no of metastatic sites N metastatic sites at baseline Mutational status OxFp therapy HR (95% CI) N All All KRAS-wt 729 0.96 (0.82, 1.12) KRAS-wt OxMdG 0/1 96 0.55 (0.35, 0.87) 0.55 (0.35, 0.87) KRAS-wt Xelox 0/1 184 1.02 (0.75, 1.40) KRAS-wt OxMdG 2+ 148 1.03 (0.73, 1.44) KRAS-wt Xelox 2+ 301 1.05 (0.83, 1.33) All All KRAS-mut 1.07 (0.90, 1.26) 565 KRAS-mut OxMdG 0/1 63 0.96 (0.57, 1.61) KRAS-mut Xelox 0/1 135 0.86 (0.60, 1.23) 116 KRAS-mut OxMdG 2+ 1.06 (0.73, 1.54) 251 KRAS-mut Xelox 2+ 1.25 (0.96, 1.61) 1 0.33 0.5 2 Favours cetuximab Favours no cetuximab

  14. Increased GI toxicity led toCapecitabine dose reductionCapecitabine dose was reduced in arm B from 1000 to 850 mg/m2 b.d. because of increased Gastrointestinal toxicity % of all randomised pts reporting diarrhoea G3+ at any time whilst on trial P-values B vs A vs OxMdG, Arm B Arm A Arm B n n OxMdG 279 11% 20% P=0.005 281 534 All 536 Xelox: 15% 26% P<0.001 P=0.030 Before dose reduction 17% 30% P<0.001 P=0.002 381 After dose reduction 16% P=0.25 P=0.41 153 12%

  15. Differentiating infusional 5FU/FA (OxMdG) and capecitabine (XELOX)

  16. 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

  17. 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 Conclusions

  18. 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 CTU • Trial Managers Sarah Kenny, Ed Kay • Statisticians David Fisher, Lindsay Thompson • Data Managers Jenna Mitchell, Laura Nichols, Cheryl Courtney, Louise Clement, Ben Sydes • Senior staff Angela Meade, Rick Kaplan, Max Parmar Lynda Harper • Trial Management Group • Co-applicants Matt Seymour, Richard Wilson, Jim Cassidy • Trial Fellows Richard Adams, Ayman Madi • Pharmacy, Nurse Elizabeth Hodgkinson, Penny Rogers • QL, HE Richard Stephens, Mark Sculpher • Patient Malcolm Pope • Medical Genetics • Cardiff Jeremy Cheadle, Chris Smith, Bharat Jasani, Michelle James, Shelley Idziaszczyk, • Wales Cancer Bank Alison Parry-Jones • Leuven Dieter Lambrechts

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