Overview of Lymphoma Clinical Trials

Transcription

1 Overview of Lymphoma Clinical Trials Dr Pam McKay Beatson West of Scotland Cancer Centre UKONS Conference November 2018

2 Clinical trials Medical research involving human participants Treatment related New treatment does it work? how does it work? is it better than standard treatment? Existing treatments comparing one treatment with another comparing different ways of using treatment e.g. doses, scheduling Pathology e.g. molecular subtypes MAPLE study Radiology e.g. use of PET/CT scans to guide treatment PETREA study Patient pathway - Horizons study Late effects e.g. fertility RATHL ovarian sub-study

3 Clinical Trials Phase 1 small trials; often aim to find best dose or test safety Phase 2 aim to find out more about the safety and effectiveness of the treatment Phase 3 larger trials; test a new treatment or a new way of using a treatment against the standard treatment Phase 4 to find out more about a drug after it has been licensed

4 Advantages Potential disadvantages Access to latest treatments Access to information Access to expert staff Careful follow up Longer follow up Helping others in future Uncertainty about outcome Might be in group with worse outcome Unexpected side effects Greatest in phase 1 trials (usually for patients with no other treatment options) Extra hospital visits Reassuring or stressful? Extra tests

5 Subtypes Hodgkin s lymphoma Diffuse Large B cell lymphoma Follicular lymphoma

6 Hodgkin s Lymphoma ABVD standard treatment for many years (70-80% cure rates) Evens et al, importance of delivering full doses on time Early stage disease ABVD 2-4 cycles + radiotherapy Can radiotherapy be omitted in patients with early stage HL who are PET negative after 3 cycles ABVD? RAPID study Advanced stage disease ABVD x 6 Can bleomycin be removed from ABVD if PET negative after 2 cycles of ABVD? RATHL study Does substitution of Brentuximab for Bleomycin improve results? ECHELON study Can we reduce toxicity of intensive escbeacopp regimen by giving less cycles if PET negative after 2 cycles? HD18 study

7 RAPID study randomization between no further treatment and radiotherapy in patients who are PET negative after 3 cycles of ABVD Radford et al, NEJM, 372;

8 RAPID study 3-year progression-free survival rate was 97.1% in the radiotherapy group and 90.8% in the group with no further therapy Modest improvement in the 3-year PFS rate (6.3%) can be obtained with the addition of radiotherapy Avoidance of RT may reduce incidence of second cancers and cardiac disease

9 RATHL 1200 advanced HL PET 1 2 cycles ABVD PET 2 PET positive PET negative Randomize 4 cycles BEACOPP-14 or 3 cycles escbeacopp PET 3 4 cycles ABVD 4 cycles AVD no bleomycin PET positive RT or salvage Johnson et al, NEJM, 374: PET negative 2 cycles BEACOPP-14 or 1 cycle escbeacopp Endpoint : PFS No further treatment No RT

10 RATHL study ~1200 patients; UK, Europe, Australia, NZ 83.7% of patients had a negative PET2 3 yr PFS 85.7% (ABVD) vs 84.4% (AVD) 3 yr OS 97.2% vs 97.6% Improved PFS in patients escalated to BEACOPP c.f. historical controls Conclusion: Bleomycin can be omitted from C3-6 with no loss of efficacy Respiratory events reduced Escalation to BEACOPP in PET + patients à improved PFS

11 Primary Endpoint: PFS for PET-negative randomized, eligible patients (Median follow up 41 months) Intention to treat analysis: Per protocol analysis: ABVD-AVD = 1.6% ( ) ABVD-AVD = 1.3% ( ) HR: 1.13 ( ), p = Year PFS, ABVD: 85.7% (95% CI: ) 3 Year PFS, AVD: 84.4% (95% CI: ) HR: 1.10 ( ), p = Year PFS, ABVD: 85.3% (95% CI: ) 3 Year PFS, AVD: 84.6% (95% CI: )

12 Overall survival: PET-2 negative patients 3 year OS ABVD: 97.2% ( ) AVD: 97.6% ( )

13 Echelon I study: ABVD v A-AVD Phase III, commercial study Untreated HL, stage III-IV ABVD v A(brentuximab)-AVD x 6 2 year modified PFS: 77.2% vs 82.1% A-AVD superior efficacy (4.9% improvement in modified PFS) Peripheral neuropathy more common with A-AVD (67% vs 43%) Serious pulmonary toxicity more common with ABVD (3% vs 1%) Connors et al, NEJM, 378;

14 Modified PFS per independent review Probability of modified PFS No. of patients at risk: A+AVD ABVD HR 0.77 (95% CI: ) Log-rank test p-value: Time from randomization (months) A+AVD ABVD Number of events Category Time A+AVD (95% CI) 2-year 82.1 ( ) Median follow-up (range): 24.9 months ( ) A+AVD N=117 ABVD (95% CI) 77.2 ( ) ABVD N=146 Progression Death Modified progression Chemotherapy Radiotherapy Connors, J. et al: Abstract no 0006, ASH 2017

15 Peripheral neuropathy and pulmonary events Treatment-emergent PN* Interstitial lung disease Patients (%) 80% 60% 40% 20% 0% 67% A+AVD Drug discontinuations due to PN: A+AVD 7% ABVD2% 43% ABVD Grade 3-4 Grade 2 Grade 1 Patients (%) % 3% 2% <1% A+AVD ABVD A+AVD ABVD Category 1 Category 2 Category 3 Category 4 All Grade 3 *Includes the preferred terms peripheral sensory neuropathy, PN, hypoesthesia, polyneuropathy, paraesthesia, muscular weakness, peripheral motor neuropathy, peroneal nerve palsy, muscle atrophy, hypotonia, autonomic neuropathy, neuralgia, burning sensation, dysesthesia, gait disturbance, toxic neuropathy, neurotoxicity, and sensory disturbance; PN, peripheral neuropathy Includes the preferred terms lung infiltration, pneumonitis, interstitial lung disease, acute respiratory distress syndrome, organizing pneumonia, pulmonary fibrosis, and pulmonary toxicity Connors, J. et al: Abstract no 0006, ASH 2017

16 Early interim PET within the German HD18 study R-eBEACOPP x 4/6* Advanced stage Hodgkin lymphoma ebeacopp x2 PET2 +ve (DS3-5) PET2 ve (DS1-2) R R ebeacopp x 4/6 ebeacopp x4/6 ebeacopp x2 HD15 Lancet May 12;379(9828) : 6 cycles more effective and less toxic than 8 (* amendment, 2011 standard treatment 6 cycles in total) Borchmann et al, 2017, Lancet. 390; Borchmann P. et al: ASH 2017 Abstract 0737

17 PFS and OS for ipet2 negative patients 5 year PFS 92% 5 year OS 97.8% Non-inferiority using 4 cycles and less infections No TRM 2.7% secondary neoplasm Borchmann et al, 2017, Lancet. 390;

18 PFS and OS for ipet2 positive patients Rituximb : no benefit 5 year PFS 88% 5 year OS 94% Borchmann et al, 2017, Lancet. 390;

19 German HD18 study - Conclusions 4 cycles ebeacopp is standard of care if PET negative after 2 cycles Rituximab is of no additional benefit

20 Current treatment of HL patients at Beatson Early stage 2-4 cycles of ABVD depending on risk factors followed by radiotherapy Discuss RAPID trial on an individual basis, especially young females Advanced stage Majority managed by RATHL approach ie ABVD x 6 with omission of bleomycin if PET scan negative after 2 cycles Consider escbeacopp as per HD18 if high prognostic score, especially in males EscBEACOPDacmay reduce infertility

21 Elderly HL - PFS with multi-agent chemotherapy Age >70 Cannot perform ADLs Andrew M. Evens et al. Blood 2012;119: by American Society of Hematology

22 BREVITY study Untreated HL Not for standard treatment due to age, frailty, co-morbidities Single agent brentuximab, 3 weekly 4 cycles then evaluate by PET/CT If CR à further 8 (total 12) If PR à further 4 then if CR, further 8 (total 16) ORR 84% (CMR or PMR at PET 4) (N=26/31) CMR rate at PET4 was 26% (N=8/31) Median PFS 7.4 months PFS for patients in CMR 11.9 months Gibb et al, ICML 2017.

23 Progression-Free Survival Tolerable therapy but high incidence of low-grade toxicity and dose reductions in this difficult-totreat population Peripheral neuropathy an issue High overall response rates but mainly partial response PFS unsatisfactory

24 The impact of treatment type and age on ovarian toxicity in the rathl study RA Anderson, R Remedios, AA Kirkwood, P Patrick, L Stevens, T Roberts, AM Carella, M Federico, A Fossa, C Hatton, N Kalakonda, DW Milligan, P McKay, J Radford, C Rowntree, F Scott, P Smith, PWM Johnson MRC Centre for Reproductive Health, The University of Edinburgh Cancer Research UK & UCL Cancer Trials Centre University College London Cancer Research UK Centre, Southampton, UK.

25 Premature Ovarian Insufficiency following treatment is an important morbidity for patients treated for Hodgkin s lymphoma Many patients present in their second or third decade Methods for preservation of female fertility are generally complex or unproven Prediction of ovarian failure at present is done by age AMH is a protein hormone produced by small growing follicles in the ovary AMH level reflects the number of primordial follicles, the Ovarian Reserve, which determines reproductive lifespan Could measurement of anti-mullerian hormone (AMH) be informative?

26 Sequential changes in AMH AB(V)D BEACOPP Baseline EOT at 1 year BEACOPP ABVD/AVD

27 Risk of premature ovarian insufficiency (POI) (defined as FSH > 25 iu/l) Women 35 or over, N (%) End of treatment 2 years Women under 35, N (%) End of treatment 2 years Median time to recovery (days) 35 or over Under 35 % Recovery at 2 years K-M estimate (95% CI) 35 or over Under 35 ABVD/AVD BEACOPP p 37 (66) 4 (10) 21 (14) % (68-86) 93% (89-96) 11 (100) 7 (70) 16 (89) 2 (20) % (19-65) 56% (36-77) 0.022* <0.001** <0.001* 0.007** 0.008*** <0.001*** * Chi squared test, ** Fisher s exact test, *** Log rank test.

28 Time to recovery of FSH below 25 iu/l

29 Can pre-treatment AMH be used to predict the risk of premature ovarian failure? FSH>10 after 1 year FSH>25 after 1 year P=0.03 P=0.12 No Yes No Yes

30 Conclusions BEACOPP regimens are significantly more toxic to ovarian function than ABVD, an effect which worsens with age There is no detectable evidence of lasting ovarian damage by ABVD in patients under 35 Reduction in AMH levels appears to be permanent following BEACOPP, although a minority of women will recover normal gonadotrophin levels Pre-treatment AMH may be a means to identify those at highest risk of POI following chemotherapy, but this requires further study with a larger cohort of patients. Anderson et al, Lancet Oncology, 19;

31 Diffuse Large B cell lymphoma (DLBCL) Commonest subtype of lymphoma Aggressive but curable 1994: 7-8 drug regimens no better than CHOP but significantly greater toxicity à CHOP is standard of care 2002: addition of rituximab to CHOP (R-CHOP) à improvement in response rates, progression free survival and overall survival by ~15% à RCHOP21 = standard of care

32 How can we improve on R-CHOP21? Chemotherapy scheduling 6 vs 8 cycles RICOVER-60 study 14 vs 21 day cycles CRUK study Different monoclonal Ab ofatumumab, obinotuzumab Goya study Additional agents bortezomib REMODL-B study ibrutinib PHOENIX study Addition of radiotherapy RICOVER-60 study Infusional chemotherapy DA EPOCH - R

33 Chemotherapy scheduling Established that 8 cycles R-CHOP no better than 6 cycles RICOVER-60 study 1 R-CHOP14 day cycle no better than 21 day cycle Pfreundschuh et al, Lancet Oncol, 9(2); Cunningham et al, Lancet, 381:

34 Different monoclonal antibody Goya study 1418 patients CHOP + Obinutuzumab (G-CHOP) vs R- CHOP Obinutuzumab anti CD20 antibody, more potent than R No difference in response rate, PFS or OS More significant toxicity with G-CHOP. OS PFS Vitolou et al, J Clin Oncol, 35(31):

35 Additional agents ABC DLBCL poorer prognosis à focus of attention Some novel agents appear to have preferential activity in ABC type Bortezomib, ibrutinib, lenalidomide in combination with R-CHOP

36 Additional agent REMODEL-B study Large phase III study, multicentre, UK 1132 patients from 109 sites First line treatment of DLBCL R-CHOP vs R-CHOP + Bortezomib No difference in outcome Phoenix study Large phase III study R-CHOP vs R-CHOP + Ibrutinib Ibrutinib - BTK inhibitor Preferential activity in ABC type DLBCL follow up ongoing

37 Addition of Radiotherapy German RICOVER-60 trial Patients aged >60 yrs 6xR-CHOP14 + 2xRituximab Value of adding radiotherapy to sites of initial bulk (>7.5cm) or extranodal disease CONRAD study

38 R-CHOP vs DA-EPOCH-R in DLBCL Phase II study, haematologica, 2012: 81% PFS at 4 yrs with DA-EPOCH-R Phase III, randomised study vs R-CHOP (SOC) 524 pts Analysis by age (<60 vs 60) and GCB vs ABC in process Preliminary analysis (all patients): no difference in EFS or OS, median FU 4.9 yrs DA-EPOCH-R more toxic Discontinuation due to ae s: 5.6 vs 1.7% Grade 4 neutropenia: 90 vs 56% Grade 4 thrombocytopenia: 35 vs 6.1% Grade 3 or 4 FEN: 37 vs 19% Grade 3 neuropathy Motor : 8 vs 1% Sensory: 15 vs 3% Wilson et al, ASH 2016, #469

39 Management of patients with poor cardiac function/multiple co-morbidities INCA study Multicentre, randomised, phase II trial 1st line DLBCL Not suitable for anthracycline due to cardiac or other co-morbidities IO-R-CVP v Gem-R-CVP IO= inotuzumab ozogamacin anti CD22 conjugated to calicheamicin (potent anti tumour antibiotic) 6 cycles, 3 weekly intervals 1y end point - PFS

40 Current management of DLBCL at Beatson R-CHOP x 6 R-CODOX-M/IVAC double hit lymphomas Consider RT if PET +ve lesion on EOT scan

41 Molecular Profiling Studies - MaPLe DLBCL newly diagnosed Samples à molecular diagnostic lab, HMDS Molecular profiling Basic clinical data collected In event of progression, patient screened for targeted treatment EZH2 mutation present à Epizyme study

42 Anthracycline cardiomyopathy: detection and prevention in high-risk cancer patients Cardiac CARE Study A multicentre prospective randomised open-label blinded end-point controlled trial of high-sensitivity cardiac troponin I-guided combination angiotensin receptor blockade and beta blocker therapy to prevent cardiac toxicity in breast cancer and lymphoma patients receiving anthracycline adjuvant therapy.

43 Patient attends clinic for diagnosis & explanation of treatment 1 month Patient is approached and agrees to participate, attends screening visit and consents to study Baseline cardiac MRI 1:1 Randomisation Anthracycline treatment cycles candesartan + carvedilol Standard care 6 months 3, 4 or 6 cycles (6, 9 or 15 weeks) Anthracycline treatment completed Post-anthracycline cardiac MRI Pre-cycle 2 ctni 6ng/L ctni concentrations recorded prior to each cycle Pre-cycle 6 ctni 23ng/L Radiotherapy (for some patients) ctni concentrations at 2, 4 and 6 months 9-20 days Titration clinics Maximum tolerated doses of candesartan + carvedilol* Drug treatment continues until final MRI scan * Target doses: Candesartan 32 mg o.d. Carvedilol 25 mg b.d.

44 Extranodal Lymphomas Primary Mediastinal B cell lymphoma IELSG 37 study Ph III, multicentre 1 st line treatment Standard of care is R chemotherapy followed by radiotherapy (RT) Can we use PET scan to determine need for RT? Secondary CNS Lymphoma MARIETTA study Systemic B-cell lymphoma with CNS involvement at diagnosis or at relapse Outlook very poor Sequential MATRIX and R-ICE, followed by highdose chemotherapy + ASCT If PET negative à randomize between RT or no further treatment

45 Relapsed DLBCL Epizyme study Phase II study, multicentre > 2 previous lines of therapy Tazemetostat (EZH2 histone methyl transferase inhibitor) Single agent, oral therapy Well tolerated ARGO study Phase II study, multicentre Patients who have relapsed post ASCT or unsuitable for transplant R + gemcitabine + oxaloplatin (RGO) vs RGO + atezolizumab (check point inhibitor)

46 Follicular lymphoma (FL) Commonest low grade lymphoma, incurable Treatment not always required at diagnosis Watch and wait Watch & wait vs rituximab study Rituximab à delay in time to require definitive treatment compared to observation alone Potential toxicity from infection Addition of rituximab to chemotherapy à improved outcomes response rates, PFS, OS Rituximab maintenance (2 monthly for 2 years) improves PFS but not OS (PRIMA study) Ardeshna et al, Lancet Oncol, 15(4);

47 PRIMA update PFS 59.2% PFS42.7% No overall survival benefit 6 yr Salles, G et al, Blood 2013, 122, by American Society of Hematology

48 Standard of care: Rituximab + chemotherapy egcvp, CHOP, bendamustine Maintenance Rituximab for 2 years Current q s: 1) Can other CD20 antibodies eg obinutuzumab result in better outcome? GALLIUM study 2) Can PET/CT scans be used to determine those patients who will not benefit from maintenance rituximab? PETREA study PRIMA study

49 GALLIUM study Large phase III study >1200 patients Comparison of obinutuzumab (O) + chemo versus rituximab (R) + chemo chemo - CHOP or CVP or bendamustine maintenance O or R for 2 years 3yr PFS 80% for O-chemo vs 73.3% for R-chemo Adverse events (gd3-5) more frequent with O (74.6 vs 67.8%) Non-lymphoma related mortality higher in bendamustine treated patients (5%) vs CHOP and CVP (<2%) Mainly infection marked reduction in CD4 helper cells persists up to 18 months Marcus et al, NEJM; 377:

50 GALLIUM study reduction in risk of PFS event Obinutuzumab + chemo approved by NICE but not SMC for 1 st line treatment

51 PETREA study R-chemotherapy (CVP, CHOP or bendamustine) PET/CT scan at diagnosis and post chemotherapy If PET/CT negative after R-chemo, randomize between maintenance R (MR) and observation If PET/CT positive after R-chemo, randomize between MR and MR + lenalidomide

52 Relapsed FL - GADOLIN Study ph 3 study, ~ 400 pts with indolent NHL (80% FL) rituximab refractory

53 Sehn et al. Lancet Oncol 2016;17(8):

54 GADOLIN update Additional 10mths FU Median PFS 25.8 (G-B) v 14.1 mths Median OS not reached (G-B) v 53.9 mths 43% reduction in risk of PD or death with G-B No new safety signals Severe neutropenia & infusion related reactions more common with G-B SMC approved Cheson et al, J Clin Oncol; 36 (22):

55 Other FL relapse studies Idelalisib in double-refractory FL, study 1,2 refractory to both rituximab and an alkylating agent* median of 4 prior therapies 1,2 56% ORR (14% CR); med PFS 11 months (in FL cohort; n=72) 2 SMC-approved toxicities REBEL study rituximab and lenalidomide +/- bendamustine Epizyme study tazemetostat multiple relapsed FL à very encouraging results especially if have EZH2 mutation (~70% RR) 1. Gopal et al, NEJM; 370 (11): ; 2. Salles et al. Haematologica, 2017 Apr; 102(4): e156 e159 *Idelalisib is licensed in Europe as monotherapy for the treatment of adult patients with follicular lymphoma (FL) that is refractory to two prior lines of treatment

56 Conclusion Clinical trials are important in improving medical care for ALL patients They may improve outcome for the individual patient They may provide treatment opportunities when standard treatment has been exhausted