1. 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 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 year 1 Diffuse large B cell lymphoma (DLBCL) accounts for 31% all NHL 2 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 >60yrs 6 1 Ferlay et al, GLOBOCAN 2001; 2 Armitage et al, JCO 1998, 3 Coiffier et al, NEJM2002. 4 Feugier et al JCO 2005; 5 Pfreundschuh et al, Lancet Oncol 2006, 6 Pfreundschuh et al, Blood 2004

4. RICOVER-60 study Pfreundschuh M; Lancet Oncol 2008 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 Does 6 or 8 cycles of R-CHOP14 improve outcomes compared to CHOP14 in patients aged 61-80? 6x CHOP14 8x CHOP14 6x R-CHOP14 8x R-CHOP14 Randomised Stage I-IV n=1222

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 Newly diagnosed CD20+ve DLBCL RANDOMISATIONRANDOMISATION R-CHOP21 CHOP21  8 cycles Rituximab  8 cycles 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 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 *International Workshop Standardised Response Criteria for NHL

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

10. Patient characteristics R-CHOP21 % (n=540) R-CHOP14 % (n=540) Age≤ 60 yrs median 47 61yrs (19-88) 48 61yrs (19-85) Gendermale54 WHO PS0-1 2 86 13 86 13 B symptomsyes4447 stageI-II III-IV 38 63 37 62 Bulky diseaseyes4952 IPI score0-1 2-3 4-5 31 53 17 31 55 17 Central review confirmed DLBCL in 96%

11. Recruitment by age 0 50 100 150 200 250 300 350 400 450 <3030-3940-4950-5960-6970-7980+ Age range Patients recruited 52%

12. Treatment administration R-CHOP21 n=462 n (%) R-CHOP14 n=481 n (%) Total no. of cycles received 0-4 5-6 7-8 33 (7) 58 (13) 379 (82)* 23 (5) 435 (91)* Total number stopped early Reasons for stopping early Toxicity Lack of response/PD/death Patient/Clinician choice Change in diagnosis Other n=89 30 28 14 6 11 n=50 23 12 5 4 6 Final data on 183 patients pending *p=0.0002

13. Patients without Rx delays R-CHOP21R-CHOP14* Cycle # treated without delay # receiving cycle # patients receiving G-CSF # treated without delay # receiving cycle 116 % 280 %28 %86 % 385 %36 %91 % 485 %40 %91 % 583 %45 %87 % 683 %48 %81 % 785 %51 %90 % (R alone) 886 %44 %95 % (R alone) *R-CHOP14: all receive G-CSF cycles 1-6

14. Toxicity during treatment Toxicity grade ≥ 3R-CHOP21 % R-CHOP14 % Neutropenia*5831 Thrombocytopenia*49 Anaemia12 Febrile neutropenia*13 (2 deaths)5 Infection 22 (1 death)18 (2 deaths) Cardiac0.42 Neurological711 Other grade 5 toxicitiesn=4 *p< 0.01 (considered significant due to multiple testing)

15. Overall response rates Based on end of treatment scan n=831 R-CHOP21 n= 405 % R-CHOP14 n=426 % CR4940 CRu1418 PR2432 SD65 PD/relapse64 CR/CRu p=0.183 6358 CR/CRu/PR p=0.139 8891 249 patients not evaluable or data missing

16. CR/CRu by characteristics n R-CHOP21 % R-CHOP14 % Age ≤ 60 (406) > 60 (425) 56 69 56 61 WHO0(443) 1(288) 2(100) 67 57 65 62 55 52 StageI/II(317) III(243) IV(260) 67 63 60 65 57 54 IPI0-1(265) 2-3(450) 4-5(116) 67 62 59 66 53 57 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 Any Cause of Deathn=150 (%) Disease103 (69) Treatment related toxicity13 (9) R-CHOP21: 6, R-CHOP14: 7 Cardiac*4 (2)* All in R-CHOP21 arm Secondary malignancy7 (5) Other18 (12) Unknown5 (3) *All cardiac deaths occurred 3-15 months after completing Rx

19. Failure-free survival: Entire cohort 2091080 EventsTotals PATIENTS at Risk 10808045753912561265880 0.0 0.2 0.4 0.6 0.8 1.0 Months from randomisation 0612182430364248 2-year FFS: 74%; 95% CI: 71%-77%

20. Overall survival: Entire cohort 1501080 EventsTotals PATIENTS at Risk 10808346214342781346180 0.0 0.2 0.4 0.6 0.8 1.0 Months from randomisation 0612182430364248 2-year OS: 81%; 95% CI: 78%-84%

21. FFS and OS by response* OS FFS 1.0 *Based on end of treatment scan (n=831)

22. FFS and OS by IPI score IPI score OS 47167 125584 37329 EventsTotals 329257194139883916 5844293012031356631 1671188049332111 0-1 2-3 4-5 0.0 0.2 0.4 0.6 0.8 1.0 Months from randomisation 061218243036 FFS 0-1 2-3 4-5 Patients at risk

23. FFS and OS by prognostic factors Failure Free Survival0verall Survival 2 year FFS %p value2 year OS %p value Age ≤60 >60 76 73 p=0.48 83 79 p=0.047 WHO 0 1 2 80 73 56 p<0.0001 87 79 63 p=<0.0001 Stage I/II III IV 81 70 68 p=0.0017 85 81 75 p=0.012 IPI score 0-1 2-3 4-5 85 72 60 p<0.0001 90 80 64 p<0.0001

24. 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 Conclusions

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