Mantle cell lymphoma An update on management

Transcription

1 Mantle cell lymphoma An update on management Dr Kim Linton Consultant Medical Oncologist The Christie NHS Foundation Trust 6 th October 2016 This educational meeting is organised and sponsored by Janssen-Cilag Ltd PHGB/MEDed/0416/0012ac October 2016

2 This meeting is organised and sponsored by Janssen-Cilag Ltd. The slide content has been reviewed by Janssen to ensure compliance with the ABPI Code of Practice for the Pharmaceutical Industry The faculty may express personal opinions that are not necessarily shared by Janssen-Cilag Ltd. Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Janssen-Cilag Ltd. on Prescribing Information is available at this meeting Janssen-Cilag Ltd Holmers Farm Way, High Wycombe, Buckinghamshire HP12 4EG

3 Disclosures I have received consultancy and / or speakers fees and / or conference sponsorship over the past 5 years from: Celgene CTI Gilead Janssen-Cilag Ltd. Pfizer Takeda

4 Rare and incurable Left image: HMRN statistics downloaded from Data shown for mantle cell lymphoma incidence as a percentage of all haematological malignancies; Right image: Abrahamsson et al, Leukaemia & Lymphoma Swedish lymphoma registry data showing overall survival in days for 785 patients diagnosed with MCL before or after 2006

5 Most not fit for intensive therapy Median age in UK is 73 years 2/3 not fit for intensive approaches 31% 69% Source: HMRN

6 European MCL Elderly trial Maintenance continued until progression Kluin Nelemans et al, NEJM Median survival not reached at median follow-up of 36 months

7 European MCL Elderly trial 4yr survival 87% for RCHOP followed by maintenance Rituximab Maintenance continued until progression Kluin Nelemans et al, NEJM Median survival not reached at median follow-up of 36 months

8 Is VR-CAP better than RCHOP? VR-CAP (LYM-3002 trial) Untreated MCL unsuitable for transplant Robak et al, NEJM patients. VR-CAP vs RCHOP: equivalent response rates (92% vs 89%) and toxicity (serious adverse events 38% vs 30%, peripheral neuropathy 30% vs 27% ). Higher CR (53% vs 42%) and PFS rates (25 vs 14 months) for VR-CAP

9 Is VR-CAP better than RCHOP? VR-CAP (LYM-3002 trial) Untreated MCL unsuitable for transplant VR-CAP NICE approved December 2015 for 1 st line treatment of adults unfit for transplant Robak et al, NEJM patients. VR-CAP vs RCHOP: equivalent response rates (92% vs 89%) and toxicity (serious adverse events 38% vs 30%, peripheral neuropathy 30% vs 27% ). Higher CR (53% vs 42%) and PFS rates (25 vs 14 months) for VR-CAP

10 Is R-bendamustine better than RCHOP? PFS Longer PFS and less toxicity bendamustine available via CDF for 1st line treatment of MCL unsuitable for standard treatment Rummel et al Lancet STiL NHL trial ; PFS data shown for MCL subgroup (94/560 patients). Comparable response rates, higher PFS and less toxicity for R-bendamustine, no survival data presented.

11 AraC prolongs survival in young patients treated intensively Can Cytarabine improve survival? Can Ara-C improve survival in the elderly? MCL1: maxichop x 4 + BEAM ASCT vs MCL2: maxichop x 3 alternating with R- ARA-C x 3 + BEAM ASCT Geisler et al, BJH year follow-up of MCL2 trial

12 R-B plus cytarabine? R-BAC 500 CGA fit pts aged with untreated MCL: Induction phase x 6 cycles q3 weeks Rituximab (375mg/m 2 ) Bendamustine (70mg/m 2 ) Cytarabine (500mg/m 2 ) Day Visco et al, 13-ICML Ongoing FIL phase ll trial of RBAC-500 in untreated MCL in the elderly. Results shown for interim analysis of 57 evaluable patients. Median age 71 (61-79) 91% advanced stage disease, 45% high MIPI, 9% blastoid. Median 5.3 cycles delivered/pt. Median FU 18 months

13 R-B plus cytarabine? R-BAC 500 CGA fit pts aged with untreated G3/4 MCL: Rituximab (375mg/m 2 ) Grade N, % 3/4 Plt, Induction phase x 6 cycles q3 weeks % FN rate, % Rx stopped due to toxicity % Bendamustine (70mg/m 2 ) Cytarabine (500mg/m 2 ) 2 year PFS compares favourably with R-B (85% vs 80%) but longer follow-up needed Day to 1 2 establish 3 4 any survival advantage Visco et al, 13-ICML Ongoing FIL phase ll trial of RBAC-500 in untreated MCL in the elderly. Results shown for interim analysis of 57 evaluable patients. Median age 71 (61-79) 91% advanced stage disease, 45% high MIPI, 9% blastoid. Median 5.3 cycles delivered/pt. Median FU 18 months

14 Inevitable relapse MCL2 regimen Rummel et al Lancet STiL NHL trial Eskelund et al, BJH year follow-up of MCL2 trial

15 Short survival for those who relapse after ASCT Relapse rate 47% at 5 years Median survival of 19 months Very short survival for relapse <12 months of ASCT Eligible patients were aged 18 years or more who underwent a first autosct for MCL between 2000 and 2009, subsequently relapsed, and were registered with the EBMT database Dietrich et al, Annals of Oncology EBMT data. ASCT = autologous stem cell transplant

16 Short survival for those who relapse after ASCT Relapse rate 47% at 5 years Median survival of 19 months Very short survival for relapse <12 months of ASCT Eligible patients were aged 18 years or more who underwent a first autosct for MCL between 2000 and 2009, subsequently relapsed, and were registered with the EBMT database Dietrich et al, Annals of Oncology EBMT data. ASCT = autologous stem cell transplant

17 Drug No. pts ORR (CR) % Options for relapsed/refractory MCL Median DOR (mo) Median PFS (mo) Median OS (mo) Reference Ibrutinib (21) NR Wang et al, NEJM 2013 R-B 2* 24* 71 (38) Rummel et al, Lancet Oncology FR 2* 23* 26 (13) Lenalidomide (5) Trněný et al, Lancet Oncology Chemotherapy (0) Temsirolimus 4 54** 22 (2) Hess et al, JCO 2009 Chemotherapy (0) NA ORR = overall response rate; DOR = duration of response; PFS = progression-free survival; OS = overall survival ; NA = not available; R-B = rituximab and bendamustine; FR = fludarabine and rituximab; mo = months; NR = not reached;*results shown for subset with mantle cell lymphoma; **results shown for 175/75mg dose group. 1 = PCYC-1104 pivotal phase ll trial; 2 = STiL trial; 3 = SPRINT trial (Single agent chemotherapy = rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine); 4 = OPTIMAL trial (single agent chemotherapy = gemcitabine, fludarabine, chlorambucil, cladribine, etoposide, cyclophosphamide, thalidomide, vinblastine)

18 Drug No. pts ORR (CR) % Options for relapsed/refractory MCL Median DOR (mo) Median PFS (mo) Median OS (mo) Reference Ibrutinib (21) NR Wang et al, NEJM 2013 R-B 2* 24* 71 (38) Rummel et al, Lancet Oncology FR 2* 23* 26 (13) Lenalidomide (5) Trněný et al, Lancet Oncology Chemotherapy (0) Temsirolimus 4 54** 22 (2) Hess et al, JCO 2009 Chemotherapy (0) NA ORR = overall response rate; DOR = duration of response; PFS = progression-free survival; OS = overall survival ; NA = not available; R-B = rituximab and bendamustine; FR = fludarabine and rituximab; mo = months; NR = not reached;*results shown for subset with mantle cell lymphoma; **results shown for 175/75mg dose group. 1 = PCYC-1104 pivotal phase ll trial; 2 = STiL trial; 3 = SPRINT trial (Single agent chemotherapy = rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine); 4 = OPTIMAL trial (single agent chemotherapy = gemcitabine, fludarabine, chlorambucil, cladribine, etoposide, cyclophosphamide, thalidomide, vinblastine)

19 Drug No. pts ORR (CR) % Options for relapsed/refractory MCL Median DOR (mo) Median PFS (mo) Median OS (mo) Reference Ibrutinib (21) NR Wang et al, NEJM 2013 R-B 2* 24* 71 (38) Rummel et al, Lancet Oncology FR 2* 23* 26 (13) Lenalidomide (5) Trněný et al, Lancet Oncology Chemotherapy (0) Temsirolimus 4 54** 22 (2) Hess et al, JCO 2009 Chemotherapy (0) NA ORR = overall response rate; DOR = duration of response; PFS = progression-free survival; OS = overall survival ; NA = not available; R-B = rituximab and bendamustine; FR = fludarabine and rituximab; mo = months; NR = not reached;*results shown for subset with mantle cell lymphoma; **results shown for 175/75mg dose group. 1 = PCYC-1104 pivotal phase ll trial; 2 = STiL trial; 3 = SPRINT trial (Single agent chemotherapy = rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine); 4 = OPTIMAL trial (single agent chemotherapy = gemcitabine, fludarabine, chlorambucil, cladribine, etoposide, cyclophosphamide, thalidomide, vinblastine)

20 Options for relapsed/refractory MCL Drug No. pts ORR (CR) % Median DOR (mo) Median PFS (mo) Median OS (mo) Reference Ibrutinib (21) NR Wang et al, NEJM 2013 R-B 2* 24* 71 (38) Rummel et al, Lancet Oncology FR 2* 23* 26 (13) Lenalidomide (5) Trněný et al, Lancet Oncology Chemotherapy (0) Temsirolimus 4 54** 22 (2) Hess et al, JCO 2009 Chemotherapy (0) NA ORR = overall response rate; DOR = duration of response; PFS = progression-free survival; OS = overall survival ; NA = not available; R-B = rituximab and bendamustine; FR = fludarabine and rituximab; mo = months; NR = not reached;*results shown for subset with mantle cell lymphoma; **results shown for 175/75mg dose group. 1 = PCYC-1104 pivotal phase ll trial; 2 = STiL trial; 3 = SPRINT trial (Single agent chemotherapy = rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine); 4 = OPTIMAL trial (single agent chemotherapy = gemcitabine, fludarabine, chlorambucil, cladribine, etoposide, cyclophosphamide, thalidomide, vinblastine)

21 Drug No. pts ORR (CR) % Options for relapsed/refractory MCL Median DOR (mo) Median PFS (mo) Median OS (mo) Reference Ibrutinib (21) NR Wang et al, NEJM 2013 R-B 2* 24* 71 (38) Rummel et al, Lancet Oncology FR 2* 23* 26 (13) Lenalidomide (5) Trněný et al, Lancet Oncology Chemotherapy (0) Temsirolimus 4 54** 22 (2) Hess et al, JCO 2009 Chemotherapy (0) NA ORR = overall response rate; DOR = duration of response; PFS = progression-free survival; OS = overall survival ; NA = not available; R-B = rituximab and bendamustine; FR = fludarabine and rituximab; mo = months; NR = not reached;*results shown for subset with mantle cell lymphoma; **results shown for 175/75mg dose group. 1 = PCYC-1104 pivotal phase ll trial; 2 = STiL trial; 3 = SPRINT trial (Single agent chemotherapy = rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine); 4 = OPTIMAL trial (single agent chemotherapy = gemcitabine, fludarabine, chlorambucil, cladribine, etoposide, cyclophosphamide, thalidomide, vinblastine)

22 Options for relapsed/refractory MCL Drug No. Licensing pts information ORR (CR) % for Median MCL NICE Median technology Median appraisals OS Reference UK availability for DOR (mo) PFS (mo) (mo) relapsed MCL Ibrutinib (21) NR Wang et al, NEJM 2013 Ibrutinib 1 r/r ID753 in progress Available via CDF R-B 2* 24* 71 (38) Rummel et al, Lancet Oncology R-B 2* B alone for r/r NHL* TA206 terminated FR 2* 23* 26 (13) Not available FR 2* Available Bortezomib (8) Goy et al, Annals of Oncology Lenalidomide 3 r/r ID739 suspended 2009 Not available Lenalidomide Chemotherapy (5) Trněný et Available al, Lancet Oncology Temsirolimus Single agent 4 83 r/r 11 (0) 10.4 TA terminated Not available chemotherapy Chemotherapy 4 Available r/r = relapsed or refractory; R=rituximab; B=bendamustine; F=fludarabine; NHL = non-hodgkin lymphoma; TA=technology appraisal; NICE = National Institute for Clinical Excellence; MCL = mantle cell lymphoma

23 Options for relapsed/refractory MCL Drug No. Licensing pts information ORR (CR) % for Median MCL NICE Median technology Median appraisals OS Reference UK availability for DOR (mo) PFS (mo) (mo) relapsed MCL Ibrutinib (21) NR Wang et al, NEJM 2013 Ibrutinib 1 r/r ID753 in progress Available via CDF R-B 2* 24* 71 (38) Rummel et al, Lancet Oncology R-B 2* B alone for r/r NHL* TA206 terminated FR 2* 23* 26 (13) Not available FR 2* Available Bortezomib (8) Goy et al, Annals of Oncology Lenalidomide 3 r/r ID739 suspended 2009 Not available Lenalidomide Chemotherapy (5) Trněný et Available al, Lancet Oncology Temsirolimus Single agent 4 83 r/r 11 (0) 10.4 TA terminated Not available chemotherapy Chemotherapy 4 Available r/r = relapsed or refractory; R=rituximab; B=bendamustine; F=fludarabine; NHL = non-hodgkin lymphoma; TA=technology appraisal; NICE = National Institute for Clinical Excellence; MCL = mantle cell lymphoma

24 Dreyling et al, Lancet 2016 Ray trial

25 Ray trial Ibrutinib Median: 14.6 months Temsirolimus Median: 6.2 months At a median follow-up of 20 months, ibrutinib reduced risk of disease progression by 57% compared with temsirolimus (HR, 0.43 [95% CI, ]; p < ) Two year PFS 41% vs 7% Dreyling et al, Lancet 2016

26 Ibrutinib effective irrespective of prior therapy lines % of patients ibrutinib 0 Ibr Tem Ibr Tem Ibr Tem CR PR 1 2 Number of prior lines of therapy 3 Rule et al. ASH 2015; Abstract 469. ORR by number of prior lines

27 Ibrutinib effective irrespective of prior therapy lines % of patients ibrutinib 0 Ibr Tem Ibr Tem Ibr Tem CR PR 1 2 Number of prior lines of therapy 3 Rule et al. ASH 2015; Abstract 469. ORR by number of prior lines

28 PFS by number lines of prior therapy % alive without progression Ibrutinib Prior Line 1 Ibrutinib Prior Line 2 Temsirolimus Prior Line 2 Temsirolimus Prior Line Patients at risk Months Ibr 1 prior Tem 1 prior Ibr 2 prior Tem 2 prior Rule et al. ASH 2015; abstract 469. PFS outcome by number of prior lines 21

29 Overall Survival Ibrutinib Median: Not yet reached Temsirolimus Median: 21.3 months No statistically significant difference in survival* (1-year survival 68% for ibrutinib vs 61% for temsirolimus) Dreyling M et al. Lancet 2016; 387(10020): *Study was not powered to detect a statistically significant difference in OS

30 R-bendamustine for relapsed MCL R-B superior to FR for ORR (38 vs 13%), median PFS (18 vs 5 months) and median survival (35 vs 21 months) Rummel M et al. Lancet Oncology 2016;. 230 patients (47 with mantle cell lymphoma)

31 R-bendamustine for relapsed MCL R-B superior to FR for ORR (38 vs 13%), median PFS (18 vs 5 months) and median survival (35 vs 21 months) Rummel M et al. Lancet Oncology 2016;. 230 patients (47 with mantle cell lymphoma)

32 Lenalidomide for relapsed MCL (SPRINT) Phase ll, randomised (SPRINT trial) 254 patients 2:1 randomisation Arm A (84 patients) Investigator s choice chemotherapy (choice of rituximab, gemcitabine, fludarabine, chlorambucil, cytarabine)* Arm B (170 patients) Lenalidomide 25mg daily on days 1-21 of a 28 day cycle Until PD or intolerability Trněný et al, Lancet Oncology The investigator agent of choice was given as follows: rituximab 375 mg/m2 intravenously on days 1, 8, 15, and 22, and then once every 56 days; gemcitabine 1000 mg/m2 intravenously on days 1, 8, and 15 every 28 days; fludarabine either 25 mg/m2 intravenously or 40 mg/m2 orally on days 1 5 every 28 days; oral chlorambucil 40 mg/m2 per month divided over 3 10 days; or cytarabine 1 2 g/m2 intravenously once or twice daily on days 1 and 2 every 28 days. Chlorambucil and rituximab were given until progressive disease, intolerance, or voluntary withdrawal; cytarabine, fludarabine, and gemcitabine were given for a maximum of six cycles.

33 Lenalidomide for relapsed MCL (SPRINT) Phase ll, randomised (SPRINT trial) 254 patients 2:1 randomisation Arm A (84 patients) Investigator s choice chemotherapy (choice of rituximab, gemcitabine, fludarabine, chlorambucil, cytarabine)* Arm B (170 patients) Lenalidomide 25mg daily on days 1-21 of a 28 day cycle Until PD or intolerability Trněný et al, Lancet Oncology The investigator agent of choice was given as follows: rituximab 375 mg/m2 intravenously on days 1, 8, 15, and 22, and then once every 56 days; gemcitabine 1000 mg/m2 intravenously on days 1, 8, and 15 every 28 days; fludarabine either 25 mg/m2 intravenously or 40 mg/m2 orally on days 1 5 every 28 days; oral chlorambucil 40 mg/m2 per month divided over 3 10 days; or cytarabine 1 2 g/m2 intravenously once or twice daily on days 1 and 2 every 28 days. Chlorambucil and rituximab were given until progressive disease, intolerance, or voluntary withdrawal; cytarabine, fludarabine, and gemcitabine were given for a maximum of six cycles.

34 Time for a risk adapted approach? Hoster et al, JCO Analysis of European MCL Network Trials using the MIPI-C

35 Time for a risk adapted approach? Less therapy? Better therapy? Hoster et al, JCO Analysis of European MCL Network Trials using the MIPI-C

36 Finding the indolent phenotype Identify and describe indolent mantle cell lymphoma Collect and analyse biopsies to define different subtypes Develop enhanced prognostic tests Primary endpoint time from diagnosis to treatment Secondary endpoint date and cause of death

37 More or less therapy and who needs it? Young & fit Low risk High risk Can a novel agent replace ASCT? Can a novel agent add value to ASCT? Elderly or frail Low risk High risk Can a novel agent replace chemo? Can a novel agent add value to chemo?

38 Summary Mantle cell lymphoma is rare and remains incurable despite therapy advances Most patients are unfit for intensive treatment Emerging options for first line treatment of patients >65 include VR-CAP, RCHOP + maintenance rituximab, R-B, R-AraC Treatment of relapsed disease is challenging; many effective treatments, including ibrutinib, lenalidomide and R-B but limited access in the UK More needs to be done, especially to develop risk adapted therapy every effort should be made to consider all patients for treatment on clinical trial