Mantle cell lymphoma An update on management

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

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 https://yellowcard.mhra.gov.uk/. Adverse events should also be reported to Janssen-Cilag Ltd. on 01494 567447 Prescribing Information is available at this meeting Janssen-Cilag Ltd. 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire HP12 4EG

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

Rare and incurable Left image: HMRN statistics downloaded from https://www.hmrn.org/statistics/incidence. Data shown for mantle cell lymphoma incidence as a percentage of all haematological malignancies; Right image: Abrahamsson et al, Leukaemia & Lymphoma 2011. Swedish lymphoma registry data showing overall survival in days for 785 patients diagnosed with MCL before or after 2006

Most not fit for intensive therapy Median age in UK is 73 years 2/3 not fit for intensive approaches 31% 69% Source: HMRN https://www.hmrn.org/statistics/incidence

European MCL Elderly trial Maintenance continued until progression Kluin Nelemans et al, NEJM 2010. Median survival not reached at median follow-up of 36 months

European MCL Elderly trial 4yr survival 87% for RCHOP followed by maintenance Rituximab Maintenance continued until progression Kluin Nelemans et al, NEJM 2010. Median survival not reached at median follow-up of 36 months

Is VR-CAP better than RCHOP? VR-CAP (LYM-3002 trial) Untreated MCL unsuitable for transplant Robak et al, NEJM 2015. 487 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

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 2015. 487 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

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 2013. STiL NHL 1-2003 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.

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 2012. 6 year follow-up of MCL2 trial

R-B plus cytarabine? R-BAC 500 CGA fit pts aged 61-80 with untreated MCL: Induction phase x 6 cycles q3 weeks Rituximab (375mg/m 2 ) Bendamustine (70mg/m 2 ) Cytarabine (500mg/m 2 ) Day 1 2 3 4 Visco et al, 13-ICML 2015. 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

R-B plus cytarabine? R-BAC 500 CGA fit pts aged 61-80 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 49 52 6 26% 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 2015. 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

Inevitable relapse MCL2 regimen Rummel et al Lancet 2013. STiL NHL 1-2003 trial Eskelund et al, BJH 2016. 15 year follow-up of MCL2 trial

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 2014. EBMT data. ASCT = autologous stem cell transplant

Drug No. pts ORR (CR) % Options for relapsed/refractory MCL Median DOR (mo) Median PFS (mo) Median OS (mo) Reference Ibrutinib 1 111 68 (21) 17.5 13.9 NR Wang et al, NEJM 2013 R-B 2* 24* 71 (38) 17.6 35.3 Rummel et al, Lancet Oncology FR 2* 23* 26 (13) 4.7 20.9 2016 Lenalidomide 3 170 40 (5) 16 8.7 27.8 Trněný et al, Lancet Oncology Chemotherapy 3 84 11 (0) 10.4 5.2 21.2 2016 Temsirolimus 4 54** 22 (2) 7.1 4.8 12.8 Hess et al, JCO 2009 Chemotherapy 4 53 2 (0) NA 1.9 9.7 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)

Options for relapsed/refractory MCL Drug No. pts ORR (CR) % Median DOR (mo) Median PFS (mo) Median OS (mo) Reference Ibrutinib 1 111 68 (21) 17.5 13.9 NR Wang et al, NEJM 2013 R-B 2* 24* 71 (38) 17.6 35.3 Rummel et al, Lancet Oncology FR 2* 23* 26 (13) 4.7 20.9 2016 Lenalidomide 3 170 40 (5) 16 8.7 27.8 Trněný et al, Lancet Oncology Chemotherapy 3 84 11 (0) 10.4 5.2 21.2 2016 Temsirolimus 4 54** 22 (2) 7.1 4.8 12.8 Hess et al, JCO 2009 Chemotherapy 4 53 2 (0) NA 1.9 9.7 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)

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 1 111 68 (21) 17.5 13.9 NR Wang et al, NEJM 2013 Ibrutinib 1 r/r ID753 in progress Available via CDF R-B 2* 24* 71 (38) 17.6 35.3 Rummel et al, Lancet Oncology R-B 2* B alone for r/r NHL* TA206 terminated FR 2* 23* 26 (13) 4.7 20.9 2016 Not available FR 2* Available Bortezomib 3 155 32 (8) 9.2 6.5 23.5 Goy et al, Annals of Oncology Lenalidomide 3 r/r ID739 suspended 2009 Not available Lenalidomide Chemotherapy 4 3 167 40 (5) 16 8.7 27.8 Trněný et Available al, Lancet Oncology Temsirolimus Single agent 4 83 r/r 11 (0) 10.4 TA207 5.2 terminated 21.2 2016 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

Dreyling et al, Lancet 2016 Ray trial

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, 0.32-0.58]; p < 0.0001) Two year PFS 41% vs 7% Dreyling et al, Lancet 2016

Ibrutinib effective irrespective of prior therapy lines 100 80 60 40 20 % of patients 71.9 24.6 47.4 48.0 46.0 2.0 68.4 18.4 50.0 39.5 37.2 2.3 75.0 11.4 63.6 33.3 33.3 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

PFS by number lines of prior therapy 100 90 % alive without progression 80 70 60 50 40 30 20 10 0 Ibrutinib Prior Line 1 Ibrutinib Prior Line 2 Temsirolimus Prior Line 2 Temsirolimus Prior Line 1 0 3 6 9 12 15 18 21 24 Patients at risk Months Ibr 1 prior 57 47 43 39 37 21 19 3 2 Tem 1 prior 50 33 24 13 11 6 4 0 0 Ibr 2 prior 82 67 58 44 40 24 15 5 3 Tem 2 prior 91 60 45 32 22 13 7 3 1 Rule et al. ASH 2015; abstract 469. PFS outcome by number of prior lines 21

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): 770-8 *Study was not powered to detect a statistically significant difference in OS

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)

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 2016. 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.

Time for a risk adapted approach? Hoster et al, JCO 2016. Analysis of European MCL Network Trials using the MIPI-C

Time for a risk adapted approach? Less therapy? Better therapy? Hoster et al, JCO 2016. Analysis of European MCL Network Trials using the MIPI-C

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

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?

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