The case for maintenance rituximab in FL

Transcription

1 New-York, October 23 rd 2015 The case for maintenance rituximab in FL Pr. Gilles SALLES

2 For FL patients, progression-free survival still needs to be improved Median R-CHVP-I 66 months P<0.001 Median CHVP-I 34 months Bachy et al,, Haematologica May 3. Rumel et al,, Lancet (9873):

3 The first randomized study using rituximab maintenance SAKK 35/98 study design FL = 202 MCL = 104 Rituximab 375mg/m² weekly x 4 FL = 151 MCL = 61 R SD,PR,CR Observation Prolonged Rituximab 375mg/m² every 2 months x 4 PD off study Ghielmini et al, Blood 103: , 2004

4 EFS in SAKK 35/98: Rituximab maintenance vs. observation

5 Maintenance in the relapse setting

6 EORTC Intergroup phase III trial in R/R Follicular Lymphoma patients PFS from 2nd randomization van Oers M, et al. J Clin Oncol. 2010;28(17):

7 EORTC Intergroup phase III trial: 5-year Overall Survival van Oers M, et al. J Clin Oncol. 2010;28(17):

8 Maintenance after autologous transplantation in relapsed FL Significant effect on PFS: HR=0. 66 multivariate analysis In pts that received pretransplant rituximab: 10 y PFS 52.1% vs. 38.7% median= 4.18 y. vs. NR No significant effect on OS 10 y OS 73.1% vs. 67.8% Pettengell, R, et al. J Clin Oncol. 2013; 31(13):

9 Maintenance in first line setting 1. After R alone

10 Rituximab vs. Watch and wait: Study design Primary endpoints: Time to initiation of new therapy (chemotherapy or radiotherapy) Effect on quality of life Asymptomatic stage 2, 3 or 4 FL Grades 1, 2 & 3a Adequate bone marrow reserve R A N D O M I S E ARM A Watchful waiting ARM B R-mono 375 mg/m 2 weekly x 4 ARM C R-mono 375 mg/m 2 weekly x 4 + maintenance q2mo for 2 years DISCONTINUED ARM A Watchful waiting ARM B X R-mono 375 mg/m 2 weekly x 4 ARM C R-mono 375 mg/m 2 weekly x 4 + maintenance q2mo for 2 years Total planned enrolment: 360 patients Ardeshna KM, et al. Blood 2010;116:Abstract 6.

11 Rituximab vs. Watch and wait Ardeshna et al. Lancet Oncol, 2014

12 E4402 (RESORT) Schema Rituximab 375 mg/m 2 qw 4 CR or PR R A N D O M I Z E Rituximab Maintenance* 375 mg/m 2 q 3 months Rituximab re-treatment at progression* 375 mg/m 2 qw 4 *Continue until treatment failure Primary Endpoint: No response to retreatment or PD within 6 months of rituximab ; Initiation of cytotoxic therapy or inability to complete treatment

13 RESORT Secondary endpoints PFS Time to chemo Kahl et al, JCO 2014.

14 RESORT Primary Endpoint: Time to Treatment Failure Kahl et al, JCO 2014.

15 Maintenance in first line setting 2. After R chemo

16 PRIMA: study design Salles G et al. Lancet. 2011; 377(9759):42-51

17 PRIMA 6 years follow-up Progression free survival from randomization 6 years = 59.2% HR= 0.57 P< years = 42.7% Median follow-up since randomization : 73 months

18 PRIMA 6 years follow-up Progression free survival from randomization R-CHOP induction R-CVP induction 62.9% 49.7% HR= P< % HR= P=.05 38% Median follow-up since randomization : 73 months

19 Rituximab maintenance obviates the adverse outcome associated with lymphoma circulating cells Observation Sarkozy C et al. Blood, 2014

20 Rituximab maintenance obviates the adverse outcome associated with lymphoma circulating cells Observation Maintenance Sarkozy C et al. Blood, 2014

21 21 1p36 deletion impact may differ according to treatment PRIMA study (patients responding to immunochemotherapy were randomized to observation or rituximab maintenance) Observation Arm Rituximab Maintenance Arm P=0.04 P=ns Is rituximab maintenance alleviating this biological effect? ns SNP arrays using Cytoscan HD Huet E & Salles G, unpublished

22 Maintenance in FL unanswered questions

23 Maintenance in FL unanswered questions? Safety during maintenance Long term side effects Efficacy of subsequent treatment(s) Maintenance and induction regimens Overall survival data Jonathan W Friedberg, Lancet 2011

24 Quality of life during Rituximab maintenance Salles G et al. Lancet. 2011; 377(9759):42-51

25 PRIMA : Infections during maintenance or observation The most common adverse events reported were grade 2 4 infections in 197 (39%) and 123 (24%) patients, respectively (estimated difference 15 1%; 95% CI %, P<0 0001). Grades 3-4 infections in respectively 5 (1%) and 22 (4%) patients The five most common infections reported in the rituximab and observation arms were bronchitis, ) upper respiratory tract infections, ) in aggregate 114 and 61 cases sinusitis, ) respectively nasopharyngitis ) and urinary tract infections (14 and 9, respectively) The cumulative number of Herpes viruses-related infections were 19 and 12, respectively Salles G et al. Lancet. 2011; 377(9759):42-51

26 Immunoglobulin levels during maintenance / observation Salles G et al. Lancet. 2011; 377(9759):42-51

27 PRIMA = 6 years follow-up Relevant causes of death OBSERVATION 58 / 518 RITUXIMAB MAINTENANCE 59 / 505 Lymphoma nd malignancies (MDS / AML) 19 (5) 6 (2) Infections * 4 7 Others 7 18 * Infections include 1 case of PML in each arm and one case of hepatitis B in R-maintenance (both reported in 2011) and one case of aspergillosis in the observation arm.

28 PRIMA 6 years follow-up Time to next treatment Median follow-up since randomization : 73 months

29 PRIMA 6 years follow-up Second line treatment Observation 518 pts Rituximab 505 pts Pts with progression % % Treated at time of progression % % With rituximab % 78 67% Without rituximab 27 16% 39 33% Detailed treatments are being further analyzed

30 PRIMA 6 years follow-up Response to second line treatment ORR CR/CRu PR 10 0 Observation Maintenance Responses reported by the investigators (percentage)

31 Maintenance in FL unanswered questions? Is any schedule better? PK data may support the scheme with one administration every 2 months Comparison about side effects? - reflects how safety data were collected

32 Rituximab maintenance after Bendamustine?

33 Overall Survival: Meta-analysis R maintenance in FL patients Vidal et al. J Natl Cancer Inst Dec 7;103(23):

34 Multivariate model Variable HR 95% CI P value Female vs. male Age >=60 vs. younger After >2 vs. first induction R-maintenance vs. no maintenance < No interaction between number of inductions and MR Vidal et al. ICML 2015

35 The major differences between PRIMA and RESORT RESORT PRIMA Tumor burden Low High Chemotherapy No Yes Depth of response after induction Median F-up 4 years 6 years Treatment at progression Rituximab, then chemo chemo (80%)

36 Maintenance and our treatment goals in follicular lymphoma Using R-maintenance, a significant benefit has been achieved to prolong PFS OS benefit is suggested from the meta-analysis data More than 60% of the patients remain free of disease and treatment 6.5 years after diagnosis 4 years after the end of maintenance