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G. A. Salles, J. F. Seymour, P. Feugier, F. Offner, A. Lopez-Guillermo, R. Bouabdallah,

Rituximab Maintenance for 2 Years in Patients with Untreated High Tumor Burden Follicular Lymphoma After Response to Immunochemotherapy. G. A. Salles, J. F. Seymour, P. Feugier, F. Offner, A. Lopez-Guillermo, R. Bouabdallah,

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G. A. Salles, J. F. Seymour, P. Feugier, F. Offner, A. Lopez-Guillermo, R. Bouabdallah,

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  1. Rituximab Maintenance for 2 Years in Patients with Untreated High Tumor Burden Follicular Lymphoma After Response to Immunochemotherapy G. A. Salles, J. F. Seymour, P. Feugier, F. Offner, A. Lopez-Guillermo, R. Bouabdallah, L. M. Pedersen, P. Brice, D. Belada, L. Xerri on behalf of the PRIMA investigators Gilles Salles Hospices Civils de Lyon & Université Claude Bernard, Lyon, France

  2. Primary RItuximab and MAintenance (PRIMA): Rationale • Although FL remains incurable, patients may benefit from prolonged remission intervals; recent progress in response rate and response duration have translated into an improved survival • Previous studies have demonstrated a significant clinical benefit using rituximab maintenance: • In relapsing patients after chemo or R-chemo • In first line patients after chemo alone or rituximab alone • … but the role of rituximab after R-chemo in first line remains unknown • PRIMA: an international and intergroup study Phase III randomized study • Coordinated by GELA, in collaboration with European and Australian study groups and individual centers in Europe, Middle East, South America, and Asia, who collected, cleaned and analyzed the data • With support from Roche

  3. PRIMA: study design INDUCTION MAINTENANCE Rituximab maintenance 375 mg/m2every 8 weeks for 2 years‡ Registration High tumor burden untreated follicular lymphoma Immunochemotherapy 8 x Rituximab +8 x CVP or 6 x CHOP or 6 x FCM CR/CRu PR Random 1:1* Observation‡ PD/SD off study * Stratified by response after induction, regimen of chemo, and geographic region ‡ Frequency of clinical, biological and CT-scan assessments identical in both arms Five additional years of follow-up

  4. PRIMA: Inclusion criteria • Patients over 18 years previously untreated with histologically confirmed follicular lymphoma grade 1, 2 or 3a • Patients with at least one of the following symptoms requiring initiationof treatment: • Bulky disease at study entry (nodal or extranodal mass > 7cm) • Involvement of ≥ 3 nodal sites (each > 3 cm) • Symptomatic splenic enlargement, compressive syndrome, pleural/peritoneal effusion • B symptoms presence • Elevated serum LDH (> ULN) or 2-microglobulin (> 3mg/L) • ECOG performance status < 2 • Written informed consent ClinicalTrials.gov: NCT00140582

  5. Transformation to high-grade lymphoma or Grade 3b follicular lymphoma Regular corticosteroids during the last 4 weeks (> 20 mg/day prednisone) Prior or concomitant malignancies Serious underlying medical conditions or poor renal or hepatic function Known HIV infection; active HBV or HCV infection Known sensitivity or allergy to murine products PRIMA: Exclusion criteria ClinicalTrials.gov: NCT00140582

  6. PRIMA: Study endpoints • Primary endpoint: • Progression-free survival (PFS)from randomization (to rituximab maintenance or observation) • Secondary endpoints: • event-free survival (EFS), overall survival (OS) • time to next anti-lymphoma treatment (TTNLT), time to next chemotherapy (TTNCT) • response rates at end of maintenance • safety and toxicity • quality of life (QoL) (FACT-G and EORTC scales) • An Independent Review Committee (IRC) also examined all response and progression data (CT scans + clinical/biological findings) ClinicalTrials.gov: NCT00140582

  7. PRIMA: Statistical assumptions • Sample size calculation: • Based on a 45% increase in median PFS, with a power of 80% to detect this difference (type I alpha risk - 2-sided - of 5%) • 1200 patients registered at induction, estimated response rate of 75%: • 900 randomized to maintenance or observation (1:1) • Full analysis after 344 events • Interim analysis planned after 258 events: • Stopping rules: two-sided O’Brien-Fleming boundary of 2.3397 with type I of 5% (nominal p = 0.0193) • Analyzed by a third party statistician and submitted to an independent Data Safety Monitoring Committee (DSMC) ClinicalTrials.gov: NCT00140582

  8. Patient disposition Patients registered: N = 1217 Induction * 15 pts in 3 sites closed prematurely Patients evaluable (N = 1202)* R-CHOP N = 885 R-CVP N = 272 R-FCM N = 45 • 9 pts did not receive chemo • 147 pts withdrew during or at the end of induction (failure to respond; toxicity) • 28 pts failed to be randomized Randomized N = 769 Randomized N = 222 Randomized N = 28 Maintenance ‡1 pt died during the randomization process Patients randomized: N = 1018‡ Rituximab N = 505 Observation N = 513

  9. Patient demographics and tumor characteristics Observation n = 513 Rituximab maintenance n = 505 58 60 56 56 54 53 51 40 36 34 33 32 32 32 30 28 Patients (%) 20 19 20 0 Median Age Male BM positive PS ECOG >0 β2m 3mg/L LDH >ULN Hb <12g/dL B symptoms (yrs) (%) (%) (%) (%) (%) (%) (%)

  10. Patient demographics and tumor characteristics (cont) Observation n = 513 Rituximab maintenance n = 505 80 76 75 70 60 50 43 42 40 Patients (%) 38 40 36 36 32 31 29 28 30 22 22 21 21 20 10 3 3 2 1 0 Low Intermediate High R-CHOP R-CVP R-FCM CR CRu PR SD/Not (≥3) (≤1) (2) evaluated FLIPI at registration Induction chemotherapy Response to induction

  11. Primary endpoint (PFS) met at the planned interim analysis Rituximab maintenance significantly reduced the risk of progression by 50% 1.0 82% Rituximab maintenance N=505 0.8 0.6 Observation N=513 66% Progression-free rate 0.4 stratified HR=0.50 95% CI 0.39; 0.64 p<.0001 0.2 0 0 6 12 18 24 30 36 Time (months) Patients at risk 505 472 443 336 230 103 18 289 195 82 15 513 469 411

  12. Benefits of rituximab maintenance seen in all major sub-groups evaluated Hazard ratio* Subgroup Hazard ratio N Category 95% CIs All 1018 0.49 0.38–0.64 All < 60 624 394 0.45 0.59 0.33–0.62 0.39–0.90 Age ≥ 60 FLIPl ≤ 1 216 370 431 0.38 0.39 0.61 0.19–0.77 0.25–0.61 0.43–0.67 FLIPl Index FLIPl = 2 FLIPl ≥ 3 R-CHOP Induction Chemotherapy 768 222 28 0.43 0.69 0.51 0.31–0.59 0.44–1.08 0.13–2.07 R-CVP R-FCM Response to Induction CR/CRu 721 290 0.52 0.45 0.38–0.70 0.29–0.72 PR 2 3 0 1 Favors maintenance Favors observation * Non-stratified analysis

  13. Consistent results across secondary endpoints Time to nextanti-lymphoma treatment Time to nextchemotherapy treatment Rituximabmaintenance Rituximabmaintenance 1.0 1.0 0.8 0.8 0.6 0.6 Event-free rate Event-free rate HR = 0.61 p = 0.0003 HR = 0.60 p = 0.0011 Observation Observation Observation Observation 0.4 0.4 0.2 0.2 0 0 0 0 6 12 18 24 30 36 0 0 6 12 18 24 30 36 Time (months) Time (months) Patients at risk 505 483 453 349 235 103 18 484 457 351 243 108 19 505 513 487 447 327 218 87 15 513 492 454 332 225 91 17

  14. Response status at end of maintenance * Patients not evaluated/missing data: respectively 16 and 22 pts ‡ not evaluated in the rituximab maintenance arm: 2 pts

  15. Safety during rituximab maintenance 100 80 Observation (n = 508) Rituximab maintenance (n = 501) 60 Patients (%) 52 40 37 35 20 23 22 16 4 4 <1 <1 <1 0 Grade ≥2 infections Any adverse event Grade 3/4adverse events Grade 3/4neutropenia Grade 3/4 infections

  16. At the time of analysis: Few patients withdrew for toxicity-related reasons during rituximab maintenance 1 patient in the observation arm 10 patients in the maintenance arm 18 and 13 deaths*, respectively, had occurred in the observation and rituximab maintenance arms 12 related to lymphoma in the observation 10 related to lymphoma in the maintenance arm Safety during rituximab maintenance (cont) (*) 3 additional deaths in the maintenance arm in patients that did not receive rituximab

  17. Summary • Rituximab maintenance for 2 years significantly improved PFS for patients with previously untreated FL who responded to induction with chemotherapy plus rituximab • Benefits of rituximab maintenance seen in all major sub-groups • Consistent improvements in secondary endpoints including EFS, TNLT, TNCT, ORR and CR rate at the end of maintenance • IRC-assessed endpoints were consistent (not shown) • Safety of maintenance was consistent with the known safety profile of rituximab, with no new or unexpected findings • Additional follow-up will allow evaluation of a possible effect on overall survival

  18. Conclusions • The benefit of rituximab maintenance in first line appears superior to that described in relapsing patients: • After R-CHOP in the EORTC study* HR = 0.69 • After R-CHOP in PRIMA HR = 0.43 • R-chemo followed by 2 years of rituximab maintenance • Represents a new standard of care for FL patients in need of treatment • Constitutes a new platform to further develop more efficient(and well tolerated) strategies * van Oers MHJ, et al. J Clin Oncol 2010; ePub ahead of print.

  19. Ackowledgements • All the investigators and their staff from 223 centers in 25 countries • Other cooperative groups in Australia/New Zealand, Spain, Czech Republic, UK and the Netherlands and several key investigators in various countries that made this study possible • The GELA and GELA-RC teams for organization, monitoring, data cleaning and statistics • Pathology review: L Xerri, N Brousse, D Canioni, F Charlotte, C Chassagne-Clément,P Dartigues, B Fabiani, L Deleval, E Campos, D DeJong • DMSC members: J Armitage, D Hasenclever, M Ghielmini • Roche team for their support, especially C Berge, J Maurer, M Mendila, M Wenger,O Manzke & S Zurfluh

  20. Backup slides

  21. PRIMA: Cox multivariate analysis PFS, Stepwise Backward Selection Procedure, n=1018

  22. Patient demography at induction

  23. Patient demography at induction (cont)

  24. Investigator-assessed response at end of induction

  25. PFS followingR-CHOP induction Benefits of rituximab maintenance seen in major sub-groups evaluated PFS followingR-CVP induction Rituximab maintenance 1.0 1.0 88% Rituximab maintenance 71% 0.8 0.8 68% 0.6 0.6 61% Event-free rate Event-free rate Observation Observation 0.4 0.4 0.2 0.2 0 0 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 Time (months) Time (months) Number left Rituximab maintenance 383 383 362 344 262 154 84 17 109 109 97 90 69 46 20 2 388 385 361 321 222 153 64 18 113 113 99 87 63 44 19 0 Observation

  26. 304 304 374 341 341 337 218 218 174 146 177 177 13 13 5 BL BL AI AI 1Y 1Y EOT EOT +1Y +1Y Rituximab maintenance does not adversely affect quality of life 100 90 80 70 60 50 Global Health Status scale 40 30 20 10 0 n Rituximab maintenance Observation BL =baseline AI = after induction 1Y = 1 year of treatment EOT = end of treatment +1Y = 1 year after end of treatment

  27. Immunoglobulin levels during maintenance / observation IgG IgA 12 6 10 3 8 Immunoglobulin A (G/L) Immunoglobulin G (G/L) 0 6 4 -3 Assess end trt Baseline Visit 3 Visit 6 Visit 12 Assess end trt Baseline Visit 3 Visit 6 Visit 12 1.5 IgM 1.2 Observation / n = 508 0.9 Rituximab / n = 501 Immunoglobulin M (G/L) 0.6 0.3 0.0 Assess end trt Baseline Visit 3 Visit 6 Visit 12

  28. Laboratory values during maintenance/observation Neutrophils Platelets 12 1000 11 900 10 800 9 700 8 600 7 Platelets (10**9/L) Neutrophils (10**9/L) 500 6 5 400 4 300 3 200 2 100 1 0 0 Base-line 2 3 4 5 6 7 8 9 10 11 12 Endtrt Base-line 2 3 4 5 6 7 8 9 10 11 12 Endtrt VISIT VISIT Lymphocytes 8 7 6 Observation / n = 508 5 Rituximab / n = 501 Lymphocytes (10**g/L) 4 3 2 1 0 Base-line 2 3 4 5 6 7 8 9 10 11 12 Endtrt VISIT

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