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

Author Disclosures No disclosures

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% 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, NEJM Feugier et al JCO 2005; 5 Pfreundschuh et al, Lancet Oncol 2006, 6 Pfreundschuh et al, Blood 2004

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

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

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

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

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

Trial recruitment 1080 patients; 119 sites Recruitment March Nov 2008

Patient characteristics R-CHOP21 % (n=540) R-CHOP14 % (n=540) Age≤ 60 yrs median 47 61yrs (19-88) 48 61yrs (19-85) Gendermale54 WHO PS B symptomsyes4447 stageI-II III-IV Bulky diseaseyes4952 IPI score Central review confirmed DLBCL in 96%

Recruitment by age < Age range Patients recruited 52%

Treatment administration R-CHOP21 n=462 n (%) R-CHOP14 n=481 n (%) Total no. of cycles received (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= n= Final data on 183 patients pending *p=0.0002

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

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)

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= CR/CRu/PR p= patients not evaluable or data missing

CR/CRu by characteristics n R-CHOP21 % R-CHOP14 % Age ≤ 60 (406) > 60 (425) WHO0(443) 1(288) 2(100) StageI/II(317) III(243) IV(260) IPI0-1(265) 2-3(450) 4-5(116) All p values for interaction >0.05

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

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

Failure-free survival: Entire cohort EventsTotals PATIENTS at Risk Months from randomisation year FFS: 74%; 95% CI: 71%-77%

Overall survival: Entire cohort EventsTotals PATIENTS at Risk Months from randomisation year OS: 81%; 95% CI: 78%-84%

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

FFS and OS by IPI score IPI score OS EventsTotals Months from randomisation FFS Patients at risk

FFS and OS by prognostic factors Failure Free Survival0verall Survival 2 year FFS %p value2 year OS %p value Age ≤60 > p= p=0.047 WHO p< p=< Stage I/II III IV p= p=0.012 IPI score p< p<0.0001

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

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

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