Midgley VICTOR ESMO presidential symposium LBA3

VICTOR: A PHASE III PLACEBO CONTROLLED
TRIAL OF ROFECOXIB IN COLORECTAL
CANCER PATIENTS FOLLOWING SURGICAL
RESECTION
Rachel SJ Midgley MD 1 , Christopher C McConkey MSc 2 , Michael J Langman
MD 23 , Justine L Smith BSc 1 , Simon A Grumett MD 4 , Patrick Julier MSc 1 ,
Claire Iveson BSc 1 , Elaine Johnstone PhD 1 , Xiao-he Chen PhD 1 , Janet A.
Dunn PhD 2 , David J Kerr MD 1 for the VICTOR Trials Group.
1 OCTO, Department of Clinical Pharmacology, University of Oxford, UK
2 Warwick Medical School Clinical Trials Unit, University of Warwick, UK
3 University of Birmingham, UK

Background
• Laboratory and case-control studies suggest a
pivotal role for the COX-2 pathway in colorectal
carcinogenesis
• The cyclo-oxygenase-2 inhibitor, rofecoxib (R), was
hypothesised to improve survival in cancer patients
who had undergone surgery for colorectal cancer
• The trial terminated early after the worldwide
withdrawal of rofecoxib over concerns about its
cardiovascular safety
• This report provides preliminary efficacy results

Eligibility
Key Inclusion Criteria
• Post R o resection of a stage II/III colorectal
carcinoma and completion of adjuvant therapy
(radiotherapy/chemotherapy/both/neither) less
than 12 weeks previously
Key Exclusion Criteria
• Patients with active peptic ulceration or gastrointestinal
bleeding
• Those receiving long-term NSAID therapy
(except low dose aspirin)

Rofecoxib 25mg OD
N = 1217
Clinical Study Design
Randomised
N = 2434
Placebo
N = 1217
• The revised protocol and statistical analysis plan
permitted detection of a reduction (HR=0.75) in
risk of death with 87% power
• Trial recruited between April 2002 and September
2004 in 151 hospitals

• Hypothesis
Translational Study Design
– SNPs may be found in or around the COX-2 gene
which may dictate response to rofecoxib
• Methods
– Single blood sample per patient collected in EDTA
– Genomic DNA extracted using QIAamp DNA
extraction kits
– Linkage disequilibrium characterised across the
PTGS2 (COX-2 gene)
– SNPs selected and genotyped (Amplifluor TM
fluorescent allele specific PCR)

Patient Characteristics
Rofecoxib
N (%)
Placebo
N (%)
Colon 791 (65.0) 802 (65.9)
Stage II 579 (47.6) 580 (47.7)
Adjuvant chemotherapy 788 (64.7) 791 (65.0)
Radiotherapy 143 (11.8) 156 (12.8)
Females 435 (35.7) 438 (36.0)
Low dose aspirin at
randomisation
105 (8.6) 84 (6.9)
Age, median (IQ range) 65 (58, 71) 65 (57, 71)

Duration of Treatment
Treatment duration Rofecoxib
N=1167
Placebo
N=1160
Treated

All CVS SAEs – Extended Follow-up
Placebo
Events
(patients)
Rofecoxib
Events
(patients)
Total
Events
(patients)
TIA / CVA 3 8 11
Ruptured cerebral aneurysm 1 0 1
Limb arterial embolus 2 1 3
DVT / PE 2 3 5
Fatal MI 0 3 3
Non-fatal MI 4 5 9
Stable angina 2 5 7
Unstable angina 2 1 3
Mural thrombus 1 0 1
Cardiac arrhythmia / block 4 3 7
Cardiac Failure (unknown cause) 1 4 5
Sudden death cardiovascular cause 2 1 3
Hypertension 0 2 2
Total 24(20) 36(36) 60(56)
fulfils thrombotic definition
P = 0.12

CVS SAEs that fulfilled thrombotic
classification
• Two sets of pre-defined published criteria were
used
• 23 confirmed cardiovascular thrombotic events
occurring within the treatment period or within 14
days after cessation
16 occurred in the rofecoxib arm
7 occurred in the placebo arm
Estimated relative risk of 2.66 (95%
confidence intervals (CI) 1.03-6.86; p=0.04)
1 Kerr et al on behalf of the VICTOR Trial Group (2007) Rofecoxib and cardiovascular
adverse events in adjuvant treatment of colorectal cancer. N Engl J Med. 26;357(4):360-9

Survival (%)
Overall Survival – Primary Outcome
100
90
80
70
60
50
40
30
20
10
0
Hazard ratio 0.94, 95% CI: (0.77 to 1.16) P=0.57
Rofecoxib (177 deaths = 14.5%)
Rofecoxib (177 deaths)
Placebo (191 deaths = 15.7%)
Placebo (191 deaths)
0 1 2 3 4 5
Years from randomisation
Number still at risk
Rofecoxib 1217 1152 1012 663 219 21
Placebo 1217 1153 1005 684 236 30

Disease-free survival (%)
100
90
80
70
60
50
40
30
20
10
0
Disease-Free Survival
Hazard ratio 0.91, 95% CI: (0.78 to 1.07) P=0.25
Rofecoxib (291 recurrences = 23.9%)
Rofecoxib (291 events)
Placebo (316 recurrences = 26.0%)
Placebo (316 events)
0 1 2 3 4 5
Years from randomisation
Number still at risk
Rofecoxib 1217 1031 824 449 114 7
Placebo 1216 1014 799 455 133 12

DFS forest plots
* 99% CI 95% CI
Events/Patients
Rofecoxib Placebo
Rofecoxib events
(O-E) Var
Stage II 80/579 105/580 -11.4 46.2
(13.8%) (18.1%)
Stage III 211/638
(33.1%)
211/637
(33.1%)
-4.4 105.2
Interaction between 2 groups = 1.4; P=.24
2
Colon 176/791 193/802 -8.3 92.2
(22.3%) (24.1%)
Rectum 91/329 97/332 -3.0 47.0
(27.7%) (29.2%)
Rectosigmoid 24/97
(24.7%)
26/83
(31.3%)
-3.5 12.4
Heterogeneity between 3 groups = 0.5; P=.79
2
Age

DFS forest plots
* 99% CI 95% CI
Events/Patients
Rofecoxib Placebo
Rofecoxib events
(O-E) Var
Adjuvant chemotherapy217/788
(27.5%)
240/791
(30.3%)
-13.6 114.1
No adjuvant chemo 74/429
(17.2%)
76/426
(17.8%)
-0.7 37.5
Interaction between 2 groups = 0.3; P=.60
2
Males 201/782
(25.7%)
216/779
(27.7%)
-9.6 104.2
Females 90/435
(20.7%)
100/438
(22.8%)
-4.8 47.5
Interaction between 2 groups = 0.0; P=.96
2
Radiotherapy 54/143
(37.8%)
57/156
(36.5%)
1.6 27.6
No radiotherapy 237/1074
(22.1%)
259/1061
(24.4%)
-14.4 123.9
Interaction between 2 groups = 0.7; P=.41
2
Low-dose aspirin at rand 35/106 19/85 5.4 13.3
(33.0%) (22.4%)
No low-dose aspirin 256/1111
(23.0%)
297/1132
(26.2%)
-20.1 138.2
Interaction between 2 groups = 3.7; P=.06
2
Year 1 117/1217
(9.6%)
145/1217
(11.9%)
-14.6 65.5
Years 2-5 174/1031
(16.9%)
171/1014
(16.9%)
0.4 86.2
Interaction between 2 groups = 1.9; P=.17
2
All patients 291/1217 316/1217 -14.2 151.7
(23.9%) (26.0%)
1
1
1
1
1
*Hazard Ratio & CI
Rofecoxib : Placebo
0.0 0.5 1.0 1.5 2.0
Rofecoxib better Placebo better
*HR & CI
Rofecoxib:Place
0.89 (0.70, 1.13)
0.98 (0.64, 1.49)
0.91 (0.71, 1.17)
0.90 (0.62, 1.31)
1.06 (0.65, 1.73)
0.89 (0.71, 1.12)
1.50 (0.74, 3.03)
0.86 (0.69, 1.08)
0.80 (0.58, 1.10)
1.00 (0.76, 1.33)
0.91 (0.78, 1.07)
(P=.25)

Conclusion from intent-to-treat analysis
• No clear overall benefit for rofecoxib
across intent-to-treat populations

COX-2 SNP genotyping results
• Sixteen variant SNPs were found in 870 patients
assessed
• Distributed across an extended genetic region
nine SNPs 5′ to the start codon
one synonymous SNP in exon 3 (Val102Val)
two intronic SNPs (introns 1 and 5)
four SNPs in the 3′ untranslated region
• 3 Variant type alleles rs10911907, rs11583191 and
rs2179555 (all in the upstream 5′ region) appeared
co-inherited to a major degree and to influence
response to rofecoxib

Recurrence according to COX-2 genotyping
Recurrence-free (%)
100
90
80
70
60
50
40
30
20
10
0
Variant, placebo
Variant, rofecoxib
Wild-type, placebo
Wild-type, rofecoxib
0 1 2 3 4 5
Years from randomisation
Number still at risk
Variant, rofecoxib 105 98 92 53 12 1
Variant, placebo 109 99 82 51 16 3
Wild-type, rofecoxib 347 330 281 172 44 5
Wild-type, placebo 302 284 230 138 41 4

Cox Multivariate Model for Recurrence
Variable Hazard ratio P
Stage II 0.56 (0.39, 0.79) 0.0009
Radiotherapy 2.16 (1.43, 3.27) 0.0003
Age (per year) 1.02 (1.00, 1.04) 0.03
Randomised to rofecoxib 0.87 (0.59, 1.27) 0.47
Variant type alleles at
rs10911907^, rs11583191^
and rs2179555^
1.57* (0.99, 2.48) 0.06
Interaction (rofecoxib*variant) 2.31** (1.06, 5.03) 0.04
^ These three variant alleles appear to be of prognostic* and predictive**
significance
25% of patients carry at least one variant allele at ALL THREE loci

Conclusions from VICTOR
• No clear overall benefit for rofecoxib across
intent-to-treat populations
• Premature closure weakened the ability of the
trial to show a benefit:
• ? too few patients to demonstrate a
clinically relevant but small effect
• ? duration of effective COX-2 inhibition may
have been inadequate to truly alter the
malignant phenotype
• There is a signal that COX-2 SNPs may affect
response to COX-2 inhibitors

Future Directions for COX-2 Trials
• Attention must be given to maintaining the
duration of therapy
• The community should decide what size of
clinical benefit would be worthwhile in a
cancer patient population, given small but
definite risk of CVS toxicity
• Inclusion / stratification according to COX-
2 SNP analysis should be considered

With thanks for the following
support:-
• Cancer Research UK for Peer Review
• UK Department of Health for personal
fellowship to Dr Rachel Midgley
• Merck and Co for unrestricted educational
grant to support the running of the study

And thanks to the following contributors:
Mr Muti Abulafi (Mayday University Hosp) - Dr Fawzi Adab (Staffordshire Gen Hosp, North Staffordshire Royal Inf) - Dr Athar Ahmad (Queen Elizabeth
Hosp King's Lynn) - Mr Simon Ambrose (St James University Hosp) - Dr Colin Askill (Singleton Hosp) - Dr Phillip Atherton (North Tyneside Gen
Hosp) - Dr Saif Awwad (Royal Shrewsbury Hosp) - Dr Ashraf Azzabi (South Tyneside District Hosp) - Dr Anne Barnes (Withybush Gen Hosp) - Dr
Christopher Baughan (St Mary's Hosp Newport) - Dr Sharon Beesley (Conquest Hosp) - Dr Kim Benstead (Gloucester Royal Hosp, Cheltenham Gen
Hosp) - Dr Eric Bessell (Nottingham City Hosp) - Dr Claire Blesing (Great Western Hosp) - Dr Christopher Bradley (Bradford Royal Inf) - Dr Alison
Brewster (Royal Gwent Hosp) - Dr John Bridgewater (North Middlesex University Hosp) - Mr William Brough (Macclesfield District Gen Hosp) - Dr
Andrew Bulman (Norfolk & Norwich University Hosp, James Paget Hosp) - Prof Jim Cassidy (Glasgow Royal Inf, Western Inf) - Dr Prabir Chakraborti
(Derbyshire Royal Inf) - Dr Mark Churn (Kidderminster Hosp, New Cross Hosp) - Dr Susan Cleator (St Mary's Hosp London) - Dr Rachel Cooper
(Dewsbury District Hosp, Pinderfields Gen Hosp) - Dr Philippa Corrie (Addenbrooke's Hosp) - Dr Fareeda Coxon (University Hosp of North Durham,
Newcastle Gen Hosp) - Dr Michael Crawford (Airedale Gen Hosp) - Dr Ann Crawshaw (Princess Royal Hosp, Queen Mary's Hosp) - Dr Thomas
Crosby (Prince Charles Hosp, Royal Glamorgan Hosp) - Prof David Cunningham (Royal Marsden Hosp Sutton) - Dr Francis Daniel (Derriford Hosp) -
Dr Werner Dobrowsky (Queen Elizabeth Hosp Gateshead, Wansbeck Gen Hosp) - Dr Martin Eatock (Belfast City Hosp) - Dr Richard Ellis (Royal
Cornwall Hosp) - Dr Stephen Falk (Bristol Haematology & Oncology Centre, Yeovil District Hosp) - Dr David Farrugia (Worcester Royal Hosp) - Prof
David Ferry (Russells Hall Hosp) - Mr Paul Finan (Leeds Gen Inf) - Mr George Foster (Countess of Chester Hosp) - Dr Alice Freebairn (Royal
Berkshire Hosp) - Dr Ian Geh (Birmingham Heartlands Hosp) - Dr Anthony Gershuny (Oldchurch Hosp) - Dr Edward Gilby (Royal United Hosp Bath) -
Dr John Glaholm (Good Hope Hosp)- Dr Rob Glynne -Jones (Mount Vernon Hosp) - Dr Simon Gollins (Glan Clwyd Hosp, Wrexham Maelor Hosp) -
Dr Peter Gomes (Princess Elizabeth Hosp Guernsey) - Dr Robert Grieve (University Hosp Walsgrave) - Mr Keith Gunning (Darlington Memorial Hosp)
- Dr Virginia Hall (Royal Hampshire County Hosp) - Dr Marcia Hall (Wexham Park Hosp) - Dr Abdel Hamid (Scunthorpe Gen Hosp, Diana Princess of
Wales Hosp) - Dr Andrew Hartley (Manor Hosp) - Dr Tamas Hickish (Poole Hosp, Royal Bournemouth Hosp) - Dr Mark Hill (Maidstone Hosp) - Mr
James Hill (Manchester Royal Inf) - Dr Joanne Hornbuckle (Weston Park Hosp) - Dr Denise Hrouda (Warwick Hosp) - Dr Tim Iveson (Royal South
Hants Hosp, Salisbury District Hosp) - Mr David Jackson (Bronglais Gen Hosp) - Dr Johnathan Joffe (Huddersfield Royal Inf) - Dr Subhash Khanna
(Leicester Royal Inf) - Dr Jonathan Ledermann (Whittington Hosp) - Dr. Martin Leslie (St Thomas' Hosp) - Dr Edward Levine (Royal Bolton Hosp) - Dr
Fiona Lofts (St George's Hosp) - Dr John Logue (Leighton Hosp) - Dr Charles Lowdell (Charing Cross Hosp) - Dr Andreas Makris (Luton &
Dunstable Hosp) - Dr Ernie Marshall (Whiston Hosp) - Prof. Timothy Maughan (Velindre Hosp) - Mr Felix Mazarelo (Trafford Gen Hosp) - Dr Karen
McAdam (Peterborough District Hosp) - Dr Fiona McKinna (Eastbourne District Gen Hosp) - Dr Timothy Meyer (Royal Free Hosp) - Dr Gary
Middleton (Royal Surrey County Hosp) - Mr Tony Miles (Worthing Hosp) - Prof John Monson (Castle Hill Hosp) - Dr Margaret Moody (West Suffolk
Hosp) - Prof Alastair Munro (Ninewells Hosp) - Dr Mark Napier (Royal Devon & Exeter Hosp, North Devon District Hosp) - Dr Jonathan Nicoll
(Cumberland Inf) - Prof John Northover (Northwick Park Hosp) - Dr Ann O'Callaghan (St Mary's Hosp Portsmouth) - Mr Richard O'Hara (Milton
Keynes Gen Hosp) - Dr Richard Osbourne (Dorset County Hosp) - Dr Ian Pedley (Sunderland Royal Hosp) - Dr Hamish Phillips (Western Gen Hosp) -
Mr Mohammad Raja (Epsom Gen Hosp) - Mr Anthony Rate (Pennine Acute Hosps NHS Trust) - Dr Daniel Rea (Queen Elizabeth Hosp Birmingham,
City Hosp Birmingham) - Dr Andrew Robertson (Southern Gen Hosp) - Dr Anne Robinson (Southend Hosp) - Dr Mark Saunders (Christie Hosp, Hope
Hosp) - Dr David Sebag-Montefiore (York District Hosp) - Dr Matt Seymour (St. James's Institute of Oncology) - Dr Karen Sherwin (Ipswich Hosp
NHS Trust) - Dr Kamran Siddiqui (Tameside Gen Hosp) - Dr David Smith (Clatterbridge Centre for Oncology, University Hosp Aintree) - Dr Michael
Snee (Pontefract GenInf) - Mr Steven Snooks (King George Hosp) - Dr Shamilla Sothi (Alexandra Hosp) - Mr Simon Stock (Noble's Hosp) - Dr
Zuzana Stokes (Lincoln County Hosp) - Prof Nick Stuart (Ysbyty Gwynedd) - Dr Arthur Sun-Myint (Southport & Formby District Gen Hosp) - Mr
Mohamed Tabaqchali (University Hosp Hartlepool, University Hosp of North Tees) - Dr Saad Tahir (Broomfield Hosp) - Dr Li Tee Tan (Hinchingbrooke
Hosp) - Dr Robert Thomas (Bedford Hosp NHS Trust) - Mr Mark Tighe (Warrington Hosp, Halton Hosp) - Dr Mary Tighe (Taunton & Somerset Hosp) -
Dr Marjorie Tomlinson (Weston Gen Hosp) - Dr Liz Toy (Torbay Hosp) - Mr JCM Van der Voet (Friarage Hosp) - Dr Nicholas Wadd (James Cook
University Hosp) - Dr Nicola Warner (Stoke Mandeville Hosp) - Dr Harpreet Wasan (Hammersmith Hosp) - Prof Alastair Watson (Royal Liverpool
University Hosp) - Dr Andrew Weaver (Churchill Hosp, Wycombe Hosp) - Dr Paula Wells (St Bartholomew's Hosp) - Dr Marie Wilkins (Royal Sussex
County Hosp) - Dr Peter Wilkinson (Stepping Hill Hosp) - Dr Gregory Wilson (Royal Albert Edward Inf) - Mr Malcolm Wilson (Withington Hosp) - Dr
Jane Worlding (George Eliot Hosp) - Dr Hosney Yosef (Hairmyres Hosp) - Mr Chu-Yiu Yui (Queen Elizabeth Hosp London).
www.octo-oxford.org.uk

Consort figure
Allocated to rofecoxib (n=1217)
Ineligibles (included in analysed populations)
- Incomplete resections (n=1)
- Randomised > 3mo after surgery
Received rofecoxib as randomised (n=1165)
Protocol violators
- Received P for first 6 months, R thereafter (n=1)
- Received wrong treatment for 3 weeks (n=1)
- Did not start treatment (n=50)
Intention to treat population: 1217
Treated population: 1217 – 50: (n = 1167) -
No follow-up (n = 13)
Lost to follow-up (n = 35, median 19 months)
Patients died (n = 177)
DFS events (n = 291)
Randomised (n=2434)
Allocated to placebo (n=1217)
Ineligibles (included in analysed populations)
- Cancer of the ileum (n=1)
- Disease before randomisation (n=1)
Randomised > 3mo after surgery (n=1)
Received placebo as randomised (n=1159)
Protocol violators
- Received R for first 6 months, P thereafter (n=1)
- Did not start treatment (n=57)
Intention to treat population: 1217
Treated population: 1217 – 57: (n = 1160)
No follow-up (n = 11)
Lost to follow-up (n = 34, median 25 months)
Patients died (n = 191)
DFS events (n = 316)

Reported Serious Adverse Events
Body system Rofecoxib Placebo P
Cardiovascular 36 24 0.12
Gastrointestinal 28 25 0.68
Respiratory 1 0 0.32
Neuropsychiatric 4 3 0.71
Infection 10 3 0.05
Other miscellaneous 13 9 0.39
Cancer 5 8 0.41
Total 97 72 0.05
• Some events reported as SAEs are not included in the table: colorectal cancer
recurrences and a single death for which no other details were available
• For the CVS, events from treatment follow-up and withdrawal forms, as well as those
gathered from SAE forms, have been included

SNPs uncovered in PTGS2 gene
Location and Schematic structure of PTGS2 gene
Solid blocks in the gene structure represent exons labelled 1 to 10, open
blocks are untranslated regions, lines between exons represent introns
Minor Allele Frequency
(%)
40
30
20
10
0
REGION
Exon3
Int5
Int1
3'UTR Gene Promoter 5'UTR
SNP
rs4648298
rs2206593
rs5275
rs20432
rs5277
rs4648261
rs20417
rs689466
rs12042763
rs2745559
rs11583191
rs2143416
rs2179555
rs10911907
rs6681231