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

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 Primary RItuximab and MAintenance (PRIMA): Rationale

PRIMA: study design PD/SD off study Rituximab maintenance 375 mg/m 2 every 8 weeks for 2 years ‡ Observation ‡ CR/CRu PR Random 1:1* Immunochemotherapy 8 x Rituximab + 8 x CVP or 6 x CHOP or 6 x FCM High tumor burden untreated follicular lymphoma INDUCTIONMAINTENANCE Registration * 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

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 initiation of 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: NCT

PRIMA: Exclusion criteria 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 ClinicalTrials.gov: NCT

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) PRIMA: Study endpoints ClinicalTrials.gov: NCT

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 with type I of 5% (nominal p = ) –Analyzed by a third party statistician and submitted to an independent Data Safety Monitoring Committee (DSMC) PRIMA: Statistical assumptions ClinicalTrials.gov: NCT

R-CHOP N = 885 Randomized N = 769 * 15 pts in 3 sites closed prematurely Patients evaluable (N = 1202)* R-CVP N = 272 Patients registered: N = 1217 R-FCM N = 45 Randomized N = 222 Randomized N = 28 Observation N = 513 Rituximab N = 505 ‡ 1 pt died during the randomization process Induction Maintenance  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 Patient disposition Patients randomized: N = 1018 ‡

Patients (%) Patient demographics and tumor characteristics Median Age (yrs) MaleBM positive (%) B symptoms (%) PS ECOG >0 (%) β2m  3mg/L (%) LDH >ULN (%) Hb <12g/dL (%) Observation n = 513Rituximab maintenance n = 505 (%)

(2) (≥3) Induction chemotherapyResponse to inductionFLIPI at registration (≤1) Patient demographics and tumor characteristics (cont) LowIntermediateHighR-CHOPR-CVPR-FCMCRCRuPRSD/Not evaluated Observation n = 513Rituximab maintenance n = 505 Patients (%)

Primary endpoint (PFS) met at the planned interim analysis Rituximab maintenance significantly reduced the risk of progression by 50% stratified HR= % CI 0.39; 0.64 p<.0001 Time (months) Rituximab maintenance N=505 Observation N= Progression-free rate % 66% Patients at risk

Benefits of rituximab maintenance seen in all major sub-groups evaluated SubgroupHazard ratio Category 95% CIs Hazard ratio* N – – – – – – – – – – – All < 60 ≥ 60 FLIPl = 2 FLIPl ≤ 1 FLIPl ≥ 3 R-CHOP R-CVP R-FCM CR/CRu PR Response to Induction Induction Chemotherapy FLIPl Index Age All * Non-stratified analysis Favors maintenanceFavors observation

Consistent results across secondary endpoints Time (months) Event-free rate Patients at risk Time (months) Event-free rate Time to next anti-lymphoma treatment Time to next chemotherapy treatment HR = 0.61 p = Rituximab maintenance Observation HR = 0.60 p = Observation Rituximab maintenance Observation

Response status at end of maintenance Observation n = 398 * Rituximab n = 389 * Progressive disease (PD)162 (40.7%)79 (20.3%) Stable disease (SD)1 (0.3%)0 (0%) Partial response (PR)29 (7.3%)28 (7.2%) Complete response (CR/CRu)190 (47.7%)260 (66.8%) * Patients not evaluated/missing data: respectively 16 and 22 pts ‡ not evaluated in the rituximab maintenance arm: 2 pts Response: end of Induction → Maintenancen = 190n = 258 ‡ Patients remaining in CR/CRu153 (56%)209 (75%) Patients converting from PR/SD to CR/CRu37 (30%)49 (45%)

Rituximab maintenance (n = 501) Observation (n = 508) Safety during rituximab maintenance Any adverse event Grade 3/4 neutropenia Grade 3/4 infections Grade ≥2 infections Patients (%) < Grade 3/4 adverse events <

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

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

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.

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

Backup slides

PRIMA: Cox multivariate analysis Covariate included in the model Hazard Ratio 95% CI for Hazard Ratio p-value Randomization treatment (R vs. O)0.50[0.39;0.64]<.0001 Age (>60 years vs. <60 years)0.54[0.49;0.83].0010 FLIPI (low vs. intermediate/high)0.62[0.42;0.90].0117 FLIPI (high vs. low/intermediate)1.42[1.08;1.87].0121 Induction treatment (R-CHOP vs R-CVP/R-FCM)0.63[0.48;0.81].0004 PFS, Stepwise Backward Selection Procedure, n=1018

Patient demography at induction R-CHOP n = 881 R-CVP n = 268 R-FCM n = 44 Male463 (53%)137 (51%)22 (50%) Female418 (47%)131 (49%)22 (50%) Age (years) at registration Mean (min–max)55.4 (22–80)57 (22–87)51.3 (29–74) Median FLIPI score 0–1193 (22%)54 (21%)7 (16%) 2312 (35%)91 (34%)20 (45%) 3–5375 (43%)122 (45%)17 (39%) n

Patient demography at induction (cont) R-CHOP n = 881 R-CVP n = 268 R-FCM n = 44 Performance status (ECOG scale) 0574 (65%)161 (60%)24 (55%) 1272 (31%)94 (35%)16 (36%) 235 (4%)13 (5%)4 (9%) Ann Arbor stage I19 (2%)4 (1%)- II68 (8%)22 (8%)5 (11%) III167 (19%)53 (20%)7 (16%) IV627 (71%)189 (71%)32 (73%)

Investigator-assessed response at end of induction R-CHOP n = 881 R-CVP n = 268 R-FCM n = 44 Responders818 (92.8%)227 (84.7%)33 (75.0%) Non-responders63 (7.2%)41 (15.3%)11 (25.0%) 95% CI for response rates[90.9; 94.5][79.8; 88.8][59.7; 86.8]

PFS following R-CHOP induction Time (months) Rituximab maintenance Observation Event-free rate Time (months) Rituximab maintenance Observation Event-free rate Observation Number left Rituximab maintenance PFS following R-CVP induction Benefits of rituximab maintenance seen in major sub-groups evaluated 88% 68% 71% 61%

Rituximab maintenance does not adversely affect quality of life Rituximab maintenance Observation Global Health Status scale BLAI+1YEOT1Y BLAI+1YEOT1Y BL =baseline AI = after induction 1Y = 1 year of treatment n EOT = end of treatment +1Y = 1 year after end of treatment

Immunoglobulin levels during maintenance / observation IgG IgA IgM Immunoglobulin G (G/L) BaselineVisit 3Visit 6Visit 12 Assess end trt Immunoglobulin A (G/L) Observation / n = 508 Rituximab / n = 501 Immunoglobulin M (G/L) BaselineVisit 3Visit 6Visit 12 Assess end trt BaselineVisit 3Visit 6Visit 12 Assess end trt

Laboratory values during maintenance/observation Neutrophils Platelets Lymphocytes Neutrophils (10**9/L) 12 Base- line End trt Platelets (10**9/L) Lymphocytes (10**g/L) Observation / n = 508 Rituximab / n = 501 VISIT Base- line End trt VISIT Base- line End trt VISIT