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

COIN Trial design OxMdG: 2 weekly IV l-folinic acid 175 mg, oxaliplatin 85mg/m 2 over 2 h, IV bolus 5-FU 400mg/m 2, 5-FU 2400mg/m 2 inf. 46 h via ambulatory pump (mFOLFOX) XELOX: 3 weekly IV oxaliplatin 130mg/m 2 over 2 h, capecitabine 1000mg/m 2 p.o. bd for 2 weeks (reduced to 850 mg/m 2 in Arm B from July 07 for toxicity) Pts/clinicians chose OxMdG or XELOX before randomisation. 5FU or capecitabine oxaliplatin Arm A CONTINUOUS CT until progression, toxicity or patient choice 5FU or capecitabine oxaliplatin cetuximab Arm B CONTINUOUS CT until progression, toxicity or patient choice FU or cap oxaliplatin FU or cap oxaliplatin FU or cap oxaliplatin Arm C INTERMITTENT CT Treat for 12 weeks then stop and monitor. Restart on progression for a further 12 weeks Second Line Chemo- therapy Irinotecan Based 815 Inclusion Advanced colorectal cancer, First line therapy, No prior chemo for metastatic disease, No prior EGFR IHC PS0-2, Good organ function COIN question 2 Is intermittent CT non-inferior? Adams poster discussion Tuesday abstract #3525

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

Baseline Characteristics All ptsKRAS wt Total randomised 2,4451,123 Choice of chemo at baseline Xelox66% OxMdG34% Sex Male65%68% Female35%32% Age median6364 ≥75 yrs9%8% WHO PS 046%47% 146%47% 28%6% Prior adjuvant chemotherapy None75%73% 1-6mo4% >6mo16%18% Yes, unspecified5% Presented for entire trial population, no significant differences were identified between arms All ptsKRAS wt Total randomised 2,4451,123 Site of primary Rectum31% Status of primary tumour Resected53%54% Unresected42%39% Local recurrence5%7% Metastases Metachronous30%32% Synchronous69%67% Liver only22%24% Liver + others53%51% Non-liver24% No. of metastatic sites 136%37% 240% > 224%22%

Mutations in Kras, Nras and Braf: distribution and prognostic significance BRAF mutation All patients Any mutation KRAS mutation KRAS wild-type All wild-type Mutation status: Median PFS (months) Arm AArm B Median OS (months) year OS (%) N: Prognostic effect of mutational status “All-wt” n=581 (44%) KRAS-mut n=565 (43%) NRAS-mut n=50 (4%) BRAF-mut n=102 (8%) Total n=1316 (81%) PopulationNArm AArm B ITT Assessed for mutations of which: - KRAS mutation - NRAS mutation - BRAF mutation 565 (43%) 50 (4%) 102 (8%) KRAS wt729 (55%) KRAS/NRAS/BRAF-wt “All wild-type” 581 (44%)289292

Grade 3-5 Toxicities and deaths Neutrophils WBC Hb Platelets Arm A Arm B * = p<0.05 ** = p<0.01 *** = p<0.001 N patients experiencing at least one CTC Grade 3+ toxicity whilst receiving COIN protocol therapy *** Hand-foot Skin rash Nail changes *** Neuropathy ** Diarrhoea Vomiting Nausea *** Stomatitis *** Anorexia low Mg *** ** Others Lethargy *** ** All ptsKRAS wt Arm AArm BArm AArm B Randomised Deaths < 60 days of randomisat’n 4.4%5.3%4.1%4.4% Safety population (started allocated treatment) % % % % All deaths ≤30 days of start of last trt. cycle 6.1%7.7%5.6%7.0% Treatm’t-rel. deaths ≤30 days of start of last trt. cycle 1.3%1.1%1.4%0.8%

Arm AArm BDiff. Median OS : mo year survival rates36.1%34.4%-1.66% Arm AArm BDiff. Median PFS: mo year survival rates8.83%9.55%+0.72% OS (primary analysis) and PFS among KRAS wild-type patients Survival B A N patients at risk: Time (months) Arm A (OxFp) Arm B (OxFp + cetux) HR point estimate = % CI = (0.90, 1.20) Χ 2 = 0.18; p = 0.68 Overall Survival Progression-free Survival Time (months) HR point estimate = % CI = (0.84, 1.09) Χ 2 = 0.27; p = 0.60 Arm A (OxFp) Arm B (OxFp + cetux)

Overall Survival: by mutation status: KRAS, NRAS, BRAF Arm AArm BDiff. Median survival:(mo) year survival rates 40.0%38.8% -1.24% B A N patients at risk: Arm AArm BDiff. Median survival: (mo) year survival rates21.2%25.5%+4.29% All wild type Any mutation Survival Time (months) Arm A (OxFp) Arm B (OxFp + cetux) HR point estimate = % CI = (0.86, 1.20) Χ 2 = 0.03; p = Time (months) Arm A (OxFp) Arm B (OxFp + cetux) HR point estimate = % CI = (0.87, 1.15) Χ 2 = 0.00; p = 0.96

Progression Free Survival: by mutation status: KRAS, NRAS, BRAF Time (months) Arm AArm BDiff. Median PFS: mo year PFS rates10.2%10.8%+0.55% Arm AArm BDiff. Median PFS: mo year PFS rates3.45%3.19%-0.26% All wild-type Any mutation Survival Arm B Arm A No at risk Time (months) Arm A (OxFp) Arm B (OxFp + cetux) HR = % CI = (0.80, 1.07) 97% CI = (0.78, 1.09) p = Arm A (OxFp) Arm B (OxFp + cetux) HR = % 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 ptsKRAS wt KRAS mut Arm AArm BArm AArm BArm AArm B N randomised Overall Response Rate at 12 weeks 45%49%50%59%41%40% Odds ratio (B vs A)OR=1.17 P=0.124 OR=1.44 P=0.015 OR=0.97 P=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=0.428 OR=1.35 P=0.049 OR=0.88 P=0.449

Significant reduction in 2nd-line treatment in the Cetuximab arm 62% 50% 56% 44% % of eligible patients Any Irinotecan 65% 53% 54% 42% AnyIrinotecan P=0.015 P=0.032 Arm A Arm B P=0.006 P=0.008 All patients KRAS wt patients Second line therapy received

0.88 (0.72, 1.08) 1.05 (0.75, 1.46) <10,000/l ≥10,000/l All pts Sex Age Met sites Fp therapy Subgroup Male Female <=65y >65y 0/1 2+ Xelox OxMdG 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 cetuximabFavours no cetuximab Interaction p-value P=0.381 P=0.222 P=0.036 P=0.103 Predefined Subgroup analyses To maximise responsiveness, sample used was “all wild-type” and outcome was PFS. WBC P=0.411

Forest plot (PFS): kras status; choice of Fp; no of metastatic sites KRAS-wt KRAS-mut Mutational status OxMdG Xelox OxMdG Xelox OxMdG Xelox OxMdG Xelox OxFp therapy 0/1 2+ 0/1 2+ N metastatic sites at baseline 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) All Favours cetuximabFavours no cetuximab

Increased GI toxicity led to Capecitabine dose reduction Capecitabine dose was reduced in arm B from 1000 to 850 mg/m 2 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= %11% P=0.030P< %15% All P=0.002P< %17% Before dose reduction P=0.41P=0.2516% 12% After dose reduction Arm A Arm B n n

Differentiating infusional 5FU/FA (OxMdG) and capecitabine (XELOX) OxMdGXELOX In Control Arm (A)Higher toxicity Neutropenia, stomatitis Higher dose intensity In combination arm (B) Maintained oxaliplatin dose intensity Higher GI toxicity Protocol reduction of capecitabine dose Reduced DI Duration of therapyNo differences with addition of cetuximab Second line therapySignificantly 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 KRAS wt 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 CTU Trial ManagersSarah Kenny, Ed Kay StatisticiansDavid Fisher, Lindsay Thompson Data ManagersJenna Mitchell, Laura Nichols, Cheryl Courtney, Louise Clement, Ben Sydes Senior staffAngela Meade, Rick Kaplan, Max Parmar Lynda Harper Trial Management Group Co-applicantsMatt Seymour, Richard Wilson, Jim Cassidy Trial FellowsRichard Adams, Ayman Madi Pharmacy, NurseElizabeth Hodgkinson, Penny Rogers QL, HERichard Stephens, Mark Sculpher Patient Malcolm Pope Medical Genetics CardiffJeremy Cheadle, Chris Smith, Bharat Jasani, Michelle James, Shelley Idziaszczyk, Wales Cancer BankAlison Parry-Jones LeuvenDieter Lambrechts