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D. Cunningham , P. Smith, P. Mouncey, W. Qian, C. Pocock, K. M. Ardeshna,

A phase III trial comparing R-CHOP 14 and R-CHOP 21 for the treatment of newly diagnosed diffuse large B cell lymphoma Results from a UK NCRI Lymphoma Group Study. D. Cunningham , P. Smith, P. Mouncey, W. Qian, C. Pocock, K. M. Ardeshna, J. Radford, J. Davies, A. McMillan, D. Linch

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D. Cunningham , P. Smith, P. Mouncey, W. Qian, C. Pocock, K. M. Ardeshna,

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  1. A phase III trial comparing R-CHOP 14 and R-CHOP 21 for the treatment of newly diagnosed diffuse large B cell lymphomaResults from a UK NCRI Lymphoma Group Study D. Cunningham, P. Smith, P. Mouncey, W. Qian, C. Pocock, K. M. Ardeshna, J. Radford, J. Davies, A. McMillan, D. Linch on behalf of the NCRI trial collaborators Abstract: 8506

  2. Author Disclosures • No disclosures

  3. Background and rationale • Non-Hodgkin lymphoma is increasing in incidence; • 287,000 cases worldwide each year1 • Diffuse large B cell lymphoma (DLBCL) accounts for 31% all NHL2 • The addition of rituximab to 6-8 cycles of CHOP21 improves overall survival of DLBCL by 9-13% 3-5 • 6 cycles of CHOP14 improved 5yr survival by 13% compared with 6 cycles of CHOP21 in patients aged >60yrs6 1Ferlay et al, GLOBOCAN 2001; 2Armitage et al, JCO 1998, 3Coiffier et al, NEJM2002. 4Feugier et al JCO 2005; 5Pfreundschuh et al, Lancet Oncol 2006, 6Pfreundschuh et al, Blood 2004

  4. RICOVER-60 study 6x R-CHOP14 6x CHOP14 Randomised Stage I-IV n=1222 8x R-CHOP14 8x CHOP14 Does 6 or 8 cycles of R-CHOP14 improve outcomes compared to CHOP14 in patients aged 61-80? • Findings • Only R-CHOP14 superior to CHOP14 in terms of event- free survival, PFS and OS(3 yr OS 78.1% vs 67.7%) • R-CHOP14 x 8 no better than R-CHOP14 x 6 Pfreundschuh M; Lancet Oncol 2008

  5. Study aim: R-CHOP14 vs 21 Does R-CHOP14 improve outcomes compared to R-CHOP21 in treatment of DLBCL?

  6. Trial design: R-CHOP14 vs 21 R-CHOP21 CHOP21  8 cycles Rituximab  8 cycles n=540 RANDOMI SAT ION Newly diagnosed CD20+ve DLBCL R-CHOP14 CHOP14  6 cycles Rituximab  8 cycles Lenograstim Day 4-12 n=540 • Stratified by • IPI (0-1, 2, 3, 4-5) • Age <60 vs. 60 • Treatment centre

  7. Major eligibility criteria • Inclusion • Age ≥ 18 years • Histologically proven CD20+ DLBCL (WHO classification) • Pathology centrally reviewed • Stages: bulky IA (>10cm), IB, II, III, IV • Previously untreated • WHO Performance status 0-2 • Normal cardiac function • Exclusion • Transformed follicular lymphoma • Previous indolent lymphoma • New diagnosis of DLBCL with some small cell infiltration in bone marrow or lymph node allowed • CNS involvement • Known to be HIV, Hepatitis B or C serology positive

  8. Outcome measures and sample size *International Workshop Standardised Response Criteria for NHL Primary: -Overall survival (OS) Secondary: -Failure free survival (FFS) -Toxicity up to 30 days post Rx -Response (CR, CRu)* Sample size: 330 events required to detect a difference of 8% in 2-year OS from 70% to 78%; a total of 1080 patients planned

  9. Trial recruitment 1080 patients; 119 sites Recruitment March 2005 - Nov 2008

  10. Patient characteristics Central review confirmed DLBCL in 96%

  11. Recruitment by age 450 400 350 300 250 Patients recruited 200 150 100 50 0 <30 30-39 40-49 50-59 60-69 70-79 80+ Age range 52%

  12. Treatment administration Final data on 183 patients pending *p=0.0002

  13. Patients without Rx delays *R-CHOP14: all receive G-CSF cycles 1-6

  14. Toxicity during treatment *p< 0.01 (considered significant due to multiple testing)

  15. Overall response rates 249 patients not evaluable or data missing

  16. CR/CRu by characteristics All p values for interaction >0.05

  17. Follow up Median follow up: 17 months Events: Deaths n=150 (14%) Total progression/relapse/death n=209 (19%)

  18. Cause of death *All cardiac deaths occurred 3-15 months after completing Rx

  19. Failure-free survival: Entire cohort 1.0 2-year FFS: 74%; 95% CI: 71%-77% 0.8 0.6 0.4 0.2 Events Totals 209 1080 0.0 0 6 12 18 24 30 36 42 48 Months from randomisation PATIENTS at Risk 1080 804 575 391 256 126 58 8 0

  20. Overall survival: Entire cohort 1.0 2-year OS: 81%; 95% CI: 78%-84% 0.8 0.6 0.4 0.2 Events Totals 150 1080 0.0 0 6 12 18 24 30 36 42 48 PATIENTS at Risk Months from randomisation 1080 834 621 434 278 134 61 8 0

  21. FFS and OS by response* 1.0 0.8 0.8 0.6 0.6 0.4 0.4 Events Totals Events Totals CR/CRu 70 504 CR/CRu 70 504 0.2 0.2 PR 44 236 PR 44 236 SD/PD/Relapse 53 91 SD/PD/Relapse 53 91 0.0 0.0 0 6 12 18 24 30 36 0 6 12 18 24 30 36 Months from randomisation Months from randomisation PATIENTS at Risk 504 468 353 247 168 87 38 CR/CRu 504 468 353 247 168 87 38 PR 236 215 155 102 67 28 14 236 215 155 102 67 28 14 SD/PD/ Relapse 91 63 34 21 12 7 5 91 63 34 21 12 7 5 FFS OS 1.0 *Based on end of treatment scan (n=831)

  22. FFS and OS by IPI score 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 Events Totals Events Totals 24 329 0-1 0-1 37 329 2-3 83 584 0.2 0.2 2-3 125 584 4-5 43 167 4-5 47 167 0.0 0.0 0 6 12 18 24 30 36 0 6 12 18 24 30 36 Months from randomisation Months fromrandomisation 329 257 194 139 88 39 16 329 264 205 149 92 41 18 584 447 330 229 149 70 32 584 429 301 203 135 66 31 167 123 86 56 37 23 11 167 118 80 49 33 21 11 FFS OS Patients at risk IPI score 0-1 2-3 4-5

  23. FFS and OS by prognostic factors

  24. Conclusions • Response rate (CR/CRu +/- PR) -6 x R-CHOP14 (+ 2 x R) no better than 8 x R-CHOP21 -No difference amongst prognostic subgroups (including IPI) • Toxicity -Non-haematological toxicities similar in both arms -More neutropenia, febrile neutropenia with R-CHOP21 -More thrombocytopenia with R-CHOP14

  25. Overall survival for the entire cohort is favourable with 80% patients still alive at 2 years from time of randomisation Final analysis will be performed when 330 deaths have occurred (predicted in Oct 2010) Conclusions

  26. Acknowledgements 119 participating centres in the UK CRUK & UCL Cancer Trials Centre Chugai Biopharmaceuticals 1080 patients and their relatives

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