YES! YES! Anton Hagenbeek, M.D., Ph.D. Anton Hagenbeek, M.D., - - PowerPoint PPT Presentation

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YES! YES! Anton Hagenbeek, M.D., Ph.D. Anton Hagenbeek, M.D., - - PowerPoint PPT Presentation

Apr 06, 2024 289 likes •558 views

IS THERE A ROLE FOR RITUXIMAB IN IS THERE A ROLE FOR RITUXIMAB IN MAINTENANCE TREATMENT IN NON- MAINTENANCE TREATMENT IN NON- FOLLICULAR INDOLENT LYMPHOMAS? FOLLICULAR INDOLENT LYMPHOMAS? YES! YES! Anton Hagenbeek, M.D., Ph.D. Anton

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SLIDE 1

Anton Hagenbeek, M.D., Ph.D. Anton Hagenbeek, M.D., Ph.D. Academic Medical Center Academic Medical Center Department of Hematology Department of Hematology University of Amsterdam University of Amsterdam Amsterdam, The Netherlands Amsterdam, The Netherlands E-mail: a.hagenbeek@amc.uva.nl E-mail: a.hagenbeek@amc.uva.nl

IS THERE A ROLE FOR RITUXIMAB IN IS THERE A ROLE FOR RITUXIMAB IN MAINTENANCE TREATMENT IN NON- MAINTENANCE TREATMENT IN NON- FOLLICULAR INDOLENT LYMPHOMAS? FOLLICULAR INDOLENT LYMPHOMAS?

YES! YES!

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SLIDE 2

NON-FOLLICULAR INDOLENT LYMPHOMAS (WHO CLASSIFICATION 2008)

  • Small lymphocytic lymphoma
  • Lymphoplasmacytic lymphoma / Waldenström
  • Extranodal marginal zone lymphoma of MALT type
  • Nodal marginal zone lymphoma
  • Splenic B-cell marginal zone lymphoma
  • Mantle cell lymphoma (?)
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SLIDE 3

BACKGROUND CONSIDERATIONS BACKGROUND CONSIDERATIONS ON THE ROLE OF RITUXIMAB ON THE ROLE OF RITUXIMAB MAINTENANCE MAINTENANCE

  • No (large) randomized trials in non-follicular

No (large) randomized trials in non-follicular indolent NHL indolent NHL

  • Non-follicular indolent NHL are included in

Non-follicular indolent NHL are included in several (positive!) trials with mainly follicular several (positive!) trials with mainly follicular NHL patients NHL patients

  • No reason to believe that R-maintenance would

No reason to believe that R-maintenance would not not benefit CD20-positive non-follicular indolent benefit CD20-positive non-follicular indolent NHL NHL

  • We all induce these patients with R-chemo

We all induce these patients with R-chemo anyway anyway

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SLIDE 4

BACKGROUND CONSIDERATIONS BACKGROUND CONSIDERATIONS ON THE ROLE OF RITUXIMAB ON THE ROLE OF RITUXIMAB MAINTENANCE (CONT’D) MAINTENANCE (CONT’D)

Thus: Thus: I defend the statement that results from R- I defend the statement that results from R- maintenance studies represent results to maintenance studies represent results to be expected in the subgroup of non- be expected in the subgroup of non- follicular indolent NHL! follicular indolent NHL!

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SLIDE 5

1.

  • 1. R-maintenance in first remission follicular NHL

R-maintenance in first remission follicular NHL

  • PRIMA study
  • PRIMA study

2.

  • 2. R-maintenance in

R-maintenance in ≥ ≥ 2 2nd

nd remission follicular NHL

remission follicular NHL

  • EORTC 20981
  • EORTC 20981

THE EVIDENCE THE EVIDENCE

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SLIDE 6

RITUXIMAB MAINTENANCE FOR 2-YEARS SIGNIFICANTLY IMPROVES THE OUTCOME OF PATIENTS WITH UNTREATED HIGH TUMOR BURDEN FOLLICULAR LYMPHOMA AFTER RESPONSE TO IMMUNOCHEMOTHERAPY: RESULTS OF THE PRIMA STUDY

  • G. Salles, J.V. Catalano, P. Feugier, F. Offner, R. Bouabdallah, D. Caballero, P.

Brice, L. Moller Pedersen, C. Haioun, D. Belada, A. Delmer, D. Simpson, H. Tilly, S. Leppa, P. Soubeyran, A. Hagenbeek, O. Casasnovas, I. Tanin, C. Ferme, M. Gomes Da Silva, C. Sebban, R. Pettengell, J. Estell, G. Milone, A. Sonnet, A. Lopez- Guillermo, J-F. Seymour, L. Xerri from France, Australia, Belgium, Spain, Denmark, Czech Republic, New Zealand, Finland, the Netherlands, Thailand, Portugal, United Kingdom, Argentina

  • n behalf of the PRIMA investigators
  • G. Salles, J.V. Catalano, P. Feugier, F. Offner, R. Bouabdallah, D. Caballero, P.

Brice, L. Moller Pedersen, C. Haioun, D. Belada, A. Delmer, D. Simpson, H. Tilly, S. Leppa, P. Soubeyran, A. Hagenbeek, O. Casasnovas, I. Tanin, C. Ferme, M. Gomes Da Silva, C. Sebban, R. Pettengell, J. Estell, G. Milone, A. Sonnet, A. Lopez- Guillermo, J-F. Seymour, L. Xerri from France, Australia, Belgium, Spain, Denmark, Czech Republic, New Zealand, Finland, the Netherlands, Thailand, Portugal, United Kingdom, Argentina

  • n behalf of the PRIMA investigators

Gilles Salles Gilles Salles Hospices Civils de Lyon Hospices Civils de Lyon & Université Claude Bernard, Lyon, France & Université Claude Bernard, Lyon, France Gilles Salles Gilles Salles Hospices Civils de Lyon Hospices Civils de Lyon & Université Claude Bernard, Lyon, France & Université Claude Bernard, Lyon, France

EHA Barcelona, June 2010 EHA Barcelona, June 2010

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SLIDE 7

PRIMA: STUDY DESIGN

PD/SD PD/SD

  • ff study
  • ff study

Rituximab maintenance 375 mg/m2 every 8 weeks for 2 years‡ Observation‡ CR/CRu PR

Random 1:1* Random 1:1*

Immunochemotherapy 8 x Rituximab + 8 x CVP or 6 x CHOP or 6 x FCM High tumor burden untreated follicular lymphoma

INDUCTION MAINTENANCE

Registration Registration * Stratified by response after induction, regimen of chemo, and geographic region * Stratified by response after induction, regimen of chemo, and geographic region

‡ ‡ Frequency of clinical, biological and CT-scan assessments identical in both arms

Frequency of clinical, biological and CT-scan assessments identical in both arms Five additional years of follow-up Five additional years of follow-up

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SLIDE 8

R-CHOP N = 885 Randomized N = 769

* * 15 pts in 3 sites closed 15 pts in 3 sites closed prematurely 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

1 pt died during the randomization process randomization process

I n d u c t i

  • n

M a i n t e n a n c e

  • 9 pts did not receive chemo

9 pts did not receive chemo

  • 147 pts withdrew during or at

147 pts withdrew during or at the end of induction (failure the end of induction (failure to respond; toxicity) to respond; toxicity)

  • 28 pts failed to be

28 pts failed to be randomized randomized

PATIENT DISPOSITION

Patients randomized: N = 1018‡

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SLIDE 9

PRIMARY ENDPOINT (PFS) MET AT THE PLANNED INTERIM ANALYSIS

Rituximab maintenance significantly reduced the risk of progression by 50%

stratified HR=0.50 stratified HR=0.50 95% CI 0.39; 0.64 95% CI 0.39; 0.64 p p<.0001 <.0001

Time (months) Time (months)

Rituximab maintenance N=505 Observation N=513

6 6 12 12 18 18 24 24 30 30 36 36 Progression-free rate Progression-free rate 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 1.0 1.0

82% 82% 66% 66%

Patients at risk Patients at risk

505 513 472 443 336 230 103 18 469 411 289 195 82 15

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SLIDE 10

CONSISTENT RESULTS ACROSS SECONDARY ENDPOINTS

513 505 487 447 327 218 87 15 483 453 349 235 103 18 Time (months) Time (months) 6 12 18 24 30 36

Event-free rate Event-free rate

0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 1.0 1.0

Patients at risk Patients at risk

513 505 492 454 332 225 91 17 484 457 351 243 108 19 Time (months) Time (months) 6 6 12 12 18 18 24 24 30 30 36 36

Event-free rate Event-free rate

0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 1.0 1.0

Time to next Time to next anti-lymphoma treatment anti-lymphoma treatment Time to next Time to next chemotherapy treatment chemotherapy treatment

HR = 0.61 HR = 0.61 p p = 0.0003 = 0.0003 Rituximab maintenance Observation HR = 0.60 HR = 0.60 p p = 0.0011 = 0.0011 Observation Rituximab maintenance Observation Observation

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SLIDE 11

Rituximab maintenance (n = 501) Rituximab maintenance (n = 501) Observation (n = 508) Observation (n = 508)

SAFETY DURING RITUXIMAB MAINTENANCE

52 37 Any adverse Any adverse event event Grade 3/4 Grade 3/4 neutropenia neutropenia Grade 3/4 Grade 3/4 infections infections Grade ≥2 Grade ≥2 infections infections Patients (%) Patients (%) 100 100 80 80 60 60 40 40 20 20 <1 4 4 <1 <1 4 4 23 Grade 3/4 Grade 3/4 adverse events adverse events <1 <1 35 22 16

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SLIDE 12

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

  • 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

  • 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

  • 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

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SLIDE 13

1.

  • 1. R-maintenance in first remission follicular NHL

R-maintenance in first remission follicular NHL

  • PRIMA study
  • PRIMA study

2.

  • 2. R-maintenance in

R-maintenance in ≥ ≥ 2nd remission follicular NHL 2nd remission follicular NHL

  • EORTC 20981
  • EORTC 20981

THE EVIDENCE THE EVIDENCE

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SLIDE 14

RITUXIMAB MAINTENANCE TREATMENT OF RITUXIMAB MAINTENANCE TREATMENT OF RELAPSED/RESISTANT FOLLICULAR NON- RELAPSED/RESISTANT FOLLICULAR NON- HODGKIN’S LYMPHOMA: LONG-TERM HODGKIN’S LYMPHOMA: LONG-TERM OUTCOME OF THE EORTC 20981 PHASE III OUTCOME OF THE EORTC 20981 PHASE III RANDOMIZED INTERGROUP STUDY RANDOMIZED INTERGROUP STUDY

Martinus H.J. van Oers, Martine van Glabbeke, Livia Martinus H.J. van Oers, Martine van Glabbeke, Livia Giurgea, Richard Klasa, Robert E. Marcus, Max Wolf, Giurgea, Richard Klasa, Robert E. Marcus, Max Wolf, Eva Kimby, Mars van ‘t Veer, Andrej Vranovsky, Eva Kimby, Mars van ‘t Veer, Andrej Vranovsky, Harold Holte and Anton Hagenbeek Harold Holte and Anton Hagenbeek

JCO 28, 2853-2858, 2010 JCO 28, 2853-2858, 2010

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SLIDE 15

EORTC 20981: RITUXIMAB MAINTENANCE VS OBSERVATION IN RELAPSED FL PATIENTS

6 x CHOP q21d

  • max. 6

cycles R-CHOP q21d

  • max. 6

cycles R A N D O M I S E D Observation 8 x R- maintenance 375 mg/m2 every 3 months for 2 years

CR, PR

van Oers MHJ, van Oers MHJ, et al. Blood et al. Blood 2006; 108:3295–3301. 2006; 108:3295–3301.

  • Relapsed/

Relapsed/ refractory FL refractory FL

  • No prior

No prior MabThera MabThera R A N D O M I S E D

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SLIDE 16
  • Induction (n = 465)

– Endpoint: response to treatment

  • Maintenance (n = 334)

– Endpoint: PFS from the date of randomisation for maintenance

  • Induction (n = 465)

– Endpoint: response to treatment

  • Maintenance (n = 334)

– Endpoint: PFS from the date of randomisation for maintenance

EORTC 20981 PHASE III TRIAL: ENDPOINTS AND FOLLOW-UP

van Oers MHJ, van Oers MHJ, et al. Blood et al. Blood 2006; 108:3295–3301. 2006; 108:3295–3301.

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SLIDE 17

van Oers MHJ, van Oers MHJ, et al. J Clin Oncol et al. J Clin Oncol 2010;28: 2853–2858. 2010;28: 2853–2858.

EORTC 20981: 6-YEAR FOLLOW-UP

  • Median follow-up from second randomization:

6 years – Proportion followed up for 3 years: 99% – Proportion followed up for 5 years: 75%

  • Median follow-up from second randomization:

6 years – Proportion followed up for 3 years: 99% – Proportion followed up for 5 years: 75%

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SLIDE 18

R-maintenance median: 44 months Observation median: 16 months 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 p p < 0.0001 < 0.0001 p p < 0.0001 < 0.0001 Time (years) Time (years) Time (years) Time (years) 20 20 40 40 60 60 80 80 100 100 PFS (%) PFS (%) PFS (%) PFS (%) PFS increase > 2.4 years PFS increase > 2.4 years PFS increase > 2.4 years PFS increase > 2.4 years

van Oers MHJ, van Oers MHJ, et al. J Clin Oncol et al. J Clin Oncol 2010;28: 2853–2858. 2010;28: 2853–2858. van Oers MHJ, van Oers MHJ, et al. J Clin Oncol et al. J Clin Oncol 2010;28: 2853–2858. 2010;28: 2853–2858.

RITUXIMAB MAINTENANCE PROLONGS PFS IN RELAPSED FL (UPDATED)

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SLIDE 19

CHOP induction CHOP induction

p p < 0.0001 < 0.0001 p p < 0.0001 < 0.0001 p p = 0.043 = 0.043 p p = 0.043 = 0.043

R-CHOP induction R-CHOP induction

R-maintenance median: 36.8 months Observation median: 11.6 months R-maintenance median: 52.7 months Observation median: 23.0 months van Oers MHJ, van Oers MHJ, et al. J Clin Oncol et al. J Clin Oncol 2010;28: 2853–2858. 2010;28: 2853–2858. van Oers MHJ, van Oers MHJ, et al. J Clin Oncol et al. J Clin Oncol 2010;28: 2853–2858. 2010;28: 2853–2858.

80 80 80 80 60 60 60 60 40 40 40 40 20 20 20 20 100 100 100 100 1 1 1 1 2 2 2 2 3 3 3 3 4 4 4 4 5 5 5 5 6 6 6 6 7 7 7 7 8 8 8 8 Time (years) Time (years) Time (years) Time (years) PFS (%) PFS (%) PFS (%) PFS (%) 80 80 80 80 60 60 60 60 40 40 40 40 20 20 20 20 100 100 100 100 Time (years) Time (years) Time (years) Time (years) 1 1 1 1 2 2 2 2 3 3 3 3 4 4 4 4 5 5 5 5 6 6 6 6 7 7 7 7 8 8 8 8

RITUXIMAB MAINTENANCE PROLONGS PFS, INDEPENDENT OF INDUCTION TREATMENT

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SLIDE 20

R-maintenance: 74% Observation: 65%

1 2 3 4 5 6 7 8

p p = 0.070 = 0.070 HR: 0.70 HR: 0.70 p p = 0.070 = 0.070 HR: 0.70 HR: 0.70 5 years Time (years) Time (years) Time (years) Time (years) Overall survival (%) Overall survival (%) Overall survival (%) Overall survival (%) 100 100 100 100 80 80 80 80 60 60 60 60 40 40 40 40 20 20 20 20

van Oers MHJ, van Oers MHJ, et al. J Clin Oncol et al. J Clin Oncol 2010;28: 2853–2858. 2010;28: 2853–2858. van Oers MHJ, van Oers MHJ, et al. J Clin Oncol et al. J Clin Oncol 2010;28: 2853–2858. 2010;28: 2853–2858.

RITUXIMAB MAINTENANCE IMPROVES OVERALL SURVIVAL (UPDATED)

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SLIDE 21

EORTC 20981 PHASE III TRIAL: CONCLUSIONS

  • Significant improvement in PFS for Rituximab

maintenance vs observation – In all patients – In all subgroups (after CHOP, after R-CHOP, CR and PR)

  • Improvement in overall survival not

statistically significant – Probably due to Rituximab salvage therapy NB: R-naive patients were enrolled in this study........

  • Significant improvement in PFS for Rituximab

maintenance vs observation – In all patients – In all subgroups (after CHOP, after R-CHOP, CR and PR)

  • Improvement in overall survival not

statistically significant – Probably due to Rituximab salvage therapy NB: R-naive patients were enrolled in this study........

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SLIDE 22

0.001 0.1 10 1000

Vidal L, et al. J Natl Cancer Inst 2009; 101:248–255.

van Oers 2006 Forstpointner 2006 Ghielmini 2004 Hainsworth 2005 Hochster 2005 Hochster 2007 Subtotal (95% CI)

HR (95% CI) HR (95% CI) Weight (%)

15.2 29.1 8.1 20.7 25.3 1.5 100

p = 0.0003

0.51 (0.31–0.86) 0.49 (0.18–1.30) 0.50 (0.27–0.92) 0.86 (0.49–1.49) 0.51 (0.25–1.04) 4.51 (0.47–43.4) 0.60 (0.45–0.79)

RITUXIMAB MAINTENANCE TREATMENT CONSISTENTLY IMPROVES OVERALL SURVIVAL

Favours Rituximab maintenance Favours observation

Study

1

40% reduction in the risk of death

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SLIDE 23

Thus: Thus:

  • R-maintenance is effective in first and

R-maintenance is effective in first and subsequent remissions / no major subsequent remissions / no major toxicity toxicity

  • Optimal schedule?

Optimal schedule?

  • Once every 2-3 months for up to 2

Once every 2-3 months for up to 2 years years

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SLIDE 24
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SLIDE 25
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SLIDE 26