Lymphoma: 2018 Novel Therapeutics for Improved Outcomes

Transcription

1 Lymphoma: 2018 Novel Therapeutics for Improved Outcomes Michael E. Williams, MD, ScM Byrd S. Leavell Professor of Medicine Chief, Hematology/Oncology Division Physician Lead, Cancer Service Line Associate Director, Clinical Affairs University of Virginia Cancer Center

2 Disclosures: Michael E. Williams, MD, ScM Clinical trial grant support to the University of Virginia: Allos, Celgene, Gilead, Janssen, Novartis, Pharmacyclics, Takeda Data Safety Monitoring Committee: Celgene Consultant: Abbvie, Astra-Zeneca, Kite, Juno, Janssen, TG Therapeutics, Gilead, Verastem, Seattle Genetics, Sandoz Scientific Advisory Board: Lymphoma Research Foundation

3 Issues in Classical HL* Old challenges Maintain high cure rates Decrease late Rx-related complications Less bleo? Less radiotherapy? New approaches to optimizing therapy PET-directed? Brentuximab in front-line? ABVD vs AAVD New approaches in relapsed/refractory Nivolumab and pembrolizumab *NS, MC, LD and Lymphocyte-rich [Not Nodular Lymphocyte Predominant HL]

4 Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin s Lymphoma Conners J.M. et al. NEJM December 2017

5 Phase III Frontline HL (ECHELON-1) Design Newly Diagnosed Advanced Stage chl Patients >18 y R Experimental Arm AVD + B-Vedotin x6 cycles Standard of Care ABVD x6 cycles Target N=1240 Primary outcome measure: Modified progression free survival (mpfs)

6 ECHELON-1: Outcome Measures/Endpoints Modified PFS Disease progression, death, modified progression (incomplete response after completion of frontline therapy according to review by independent committee, followed by subsequent anticancer therapy) Timing of the modified progression event was the date on which the first PET scan was obtained after completion of frontline therapy, showing the absence of complete response. In the absence of disease progression, a switch to an alternative frontline therapy before completion of primary chemotherapy with the randomized regimen was not considered to be an event.

7 ECHELON-1: Results Connors J.M. et al. NEJM Dec 2017

8 ECHELON-1: Conclusions A+AVD vs ABVD in Stage III/IV HD had an improved modified PFS: difference at 2 years of 4.9% Benefit of A+AVD in subgroups > 1 extranodal site, high IPS indicating high risk for treatment failure (4 to 7), and patients with stage IV disease Peripheral neuropathy (grade 3 or higher) was increased in A+AVD by 9%, but 67% were reversible. Reduced the need for subsequent anti-lymphoma therapy A+AVD regimen is associated with more myelotoxicity, use of G-CSF is recommended

9 ECHELON-1: Take-Home. AAVD is an important front-line therapy for advancedstage chl Should consider in high-risk and younger patients Interim PET after 2 cycles of ABVD correlates with outcome: if PET2 negative (Deauville 1-3) à omit bleo in cycles 3-6 Cost of AAVD higher: brentuximab (BV) and G-CSF Avoid bleo in patients > 70 y Consider BV alone or with Dacarabazine in the elderly Rutherford, Leonard. JAMA Oncology August 2018; Friedberg et al. Blood October 2017

10 Diffuse Large B-cell Lymphoma

11 DA-R-EPOCH vs R-CHOP CALGB Untreated, de novo DLBCL Target N=478, increased to 523 Powered on EFS Enrollment from 5/2005-5/2013 No difference in disease characteristics between arms 86% vs 79% of Pts completed RCHOP vs. EPOCH (significant) 6.5% EPOCH d/c ed early due to AE ORR same: 89% CR 62%, PR 27% * Treatment-related deaths (5 in each arm) R-CHOP CHF (1), CNS bleed (1), infection (1), F/N (1), unknown (1) DA-EPOCH R infection (2), MI (1), unknown (2) Bartlett N, et al. ASH 2016

12 DA-R-EPOCH vs R-CHOP CALGB Bartlett N ASH 2016

13 DA-R-EPOCH vs R-CHOP CALGB Problems with this study Increased ratio of lower-risk IPI patients on this study Required repeat biopsy for fresh frozen tissue As a result, patients with higher risk presentations and in need of immediate therapy were less represented Patients in R-CHOP arm did better than expected If DA-R-EPOCH is going to move forward, it will need to be in subtypes where R-CHOP doesn t work Bartlett N, et al. ASH 2016

14 Biology of DLBCL Targeting disease subsets Study Intervention Cohort Enrolling? E1411 R2 [Lenalidimide] -CHOP vs. RCHOP All DLBCL Enrolled, pending report ROBUST R2CHOP vs. RCHOP ABC by Lymph2Cx Enrolled, pending report Jansen study Ibrutinib RCHOP vs. RCHOP Non-GCB by IHC Enrolled pending report PYRAMID Bortezomib- RCHOP vs. RCHOP Non-GCB by IHC Reported, negative GOYA G[Obinutuzumab]-CHOP vs. RCHOP All DLBCL Reported, negative PRELUDE RCHOP vs. RCHOP + Enzastaurin maintenance High risk DLBCL Reported, negative RAD-001 RCHOP vs. RCHOP + everolimus maintenance High risk DLBCL Reported, negative REMARC RCHOP vs. RCHOP + Len maintenance Elderly DLBCL Reported, negative Goy A, JCO :

15 What targeted therapies should be considered now for DLBCL? Front-line therapy: RR-CHOP (stay tuned) Relapsed/Refractory, non-sct eligible or relapse post-asct, not a trial candidate: CAR-T-cell therapy R 2 : Lenalidomide/Rituximab Ibrutinib: especially in non-gcb Copanlisib: consider in GCB, transformed FL Brentuximab vedotin: If CD30+

16 Cooperative Group Strategies Identify patient with DLBCL Submit tissue to a pre-study to determine COO and double hit Give a cycle of RCHOP For C2, enroll in another study with information from prestudy Others? High risk, Double hit -EPOCH based trial Standard risk -RCHOP based study -? Biologically driven Frail/Elderly -mini-r-chop based study Problems with this strategy: TISSUE!!

17 Mantle Cell Lymphoma

18 MCL Challenges Impact of biologic heterogeneity Treatment endpoints: MRD? Improve duration of response Minimize/optimize use of ASCT Incorporate novel agents into front line Chemo-free regimens Intermittent treatment with novel agents Cure

19 MCL Initial Therapy: 2018 Standard of care not established Younger, fit patient Rituximab plus a high-dose cytarabine - based regimen à ASCTà Maint Rituximab Older or serious coexisting illness Rituximab - Bendamustine R-CHOP àmaintenance R q 2 mo x 2-3 yr R2 (Lenalidomide plus Rituximab) VR-CAP (Bortezomib plus R-CHOP, no vincristine) Clinical trial preferred

20 Abstract # 145 ASH 2016

21 LyMa trial W1 W4 W7 W10 OBSERVATION R-DHAP R-DHAP R-DHAP R-DHAP R-DHAPR-BEAM If < VGPR R-CHOP If > VGPR RITUXIMAB MAINTENANCE every 2 months during 3 years R-DHAP: Rituximab 375mg/m2; aracytine 2g/m2 x2 IV 3 hours injection 12hours interval; dexamethasone 40mg d1-4; Cisplatin 100mg/m2 d1 (or oxaliplatin or carboplatin) R-BEAM: Rituximab 500mg/m2 d-8; BCNU 300mg/m2 d-7; Etoposide 400mg/m2/d d-6 to -3; aracytine 400mg/m2/d d-6 to d-3; melphalan 140mg/m2 d-2

22 Disease status at randomization Disease status-no.(%) (according to Cheson 99) AFTER R-DHAP Observation n=120 Rituximab maintenance n=120 ORR 117 (97.5) 119 (99.2) CR/CRu 104 (86.7) 102 (85) AFTER ASCT ORR 120 (100) 119 (99.2) CR/CRu 110 (91.7) 113 (94.2)

23 PFS from Randomization mfu: 50.2m ( ) PFS Obs (95%CI) vs Rituximab (95%CI) 24m: 79.8 % ( ) 93.3 % ( ) 36m: 72.8 % ( ) 89.1 % ( ) 48m: 64.6 % ( ) 82.2 % ( ) PFS (months) from randomization

24 OS from Randomization mfu: 50.2m ( ) OS Obs (95%CI) vs Rituximab (95%CI) 24m: 93.3 % ( ) 93.3 % ( ) 36m: 85.4 % ( ) 93.3 % ( ) 48m: 81.4 % ( ) 88.7 % ( ) OS (months) from randomization

25 Relapsed MCL: A typical presentation in our practice Older patient who received R-CHOP or R- Bendamustine, then maintenance R Now relapsed, declines clinical trial, not a transplant candidate Our current approach: Ibrutinib or acalabrutinib Lenalidomide plus Rituximab Bortezomib +/- rituximab

26 BTK Inhibitors

27 PFS and OS by Prior Line of Therapy Pooled analysis of 3 Ibrutinib studies in Relapsed/Refractory MCL (n=370) PFS OS Median 33.6 mo ( ) Median NR (36.0-NE) Median 8.4 mo ( ) Median 22.5 mo ( ) Median PFS overall (95% CI): 13.0 ( ) Median OS overall (95% CI): 26.7 ( ) months months Median PFS was nearly 3 years in patients with 1 prior line of therapy Patients censored from OS analysis upon study discontinuation. CI, confidence interval; NE, not estimable. S. Rule, et al. Brit J Haematol 2017

28 Conclusions: Ibrutinib in R/R MCL In a mature pooled data set of 370 R/R MCL patients across 3 studies: Median PFS was nearly 3 y for pts with 1 prior line of therapy Median PFS was nearly 4 y for pts achieving CR, and median DOR was 55 months CR rate increases over time with continued ibrutinib therapy New onset grade 3 adverse events: were most common in the first year were less common in patients with 1 prior line of therapy Rule S, et al. Brit J Haematol 2017

29 Ibrutinib activity in other NHL CLL/SLL U.S. FDA approved indication Lymphoplasmacytic/Waldenstrom -FDA approved 91% of 63 relapsed pts responded high response in MYD88 mutated/cxcr4 wild type (Treon et al, NEJM 2015; 372: ) Ibrutinib-Rituximab highly active (ASCO and NEJM 2018) Relapsed/refractory non-gcb DLBCL 14/38 responses (6 CR) vs 1/20 GCB subtype (Wilson et al, Nature Med 2015;21:922-6) Primary CNS lymphoma FL ~30% ORR in R/R pts, median PFS 10 months (Bartlett et al, Blood 2018)

30 Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, phase 2 trial Wang M, et al. Lancet 2018; 391:

31 Lenalidomide

32 MCL-001: Efficacy of Lenalidomide Goy, Singha, Williams et al, JCO 2013 Efficacy Parameter (N = 134) Central Review, n (%) Investigator Review, n (%) ORR* 37 (28) 43 (32) CR/CRu 10 (7.5) 22 (16) PR 27 (20) 21 (16) SD 39 (29) 36 (27) PD 35 (26) 43 (32) Median DOR, months (95% CI) 16.6 ( ) 18.5 ( ) Median DOR for CR/CRu, months (95% CI) 16.6 (16.6-NR) 26.7 (16.8-NR) All patients relapsed, all had prior bortezomib therapy NR, not reached. *No response assessments were available for 23 patients (central) and 12 patients (investigator). Goy et al. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 905.

33 Sustained remission with Lenalidomide plus Rituximab as initial therapy of MCL J Ruan et al, NEJM 2015 n=38, median f/u 30 mo. (10-42 mo.) ORR 92%, CR 64% (by PET +/- BM; med. 11 mo. to reach CR) 2 yr PFS 85%, 2 yr OS 97% 26 pts remain on maintenance No difference if Low- vs High-risk MIPI No correlation with Ki-67 score Toxicity: Grade 3-4 neutropenia 50%, thrombocytopenia 13% 1 pancreas cancer, 6 non-inv. skin cancer Grade 3 infection in 3 pts Relapsing pts responded to second line Rx

34 BCL2 inhibitor: Venetoclax

35 Venetoclax (ABT-199) is BCL-2 specific: limited activity in FL but high response rate in MCL FL = all responses occurred at doses 600 mg (4/8 patients; 50%) 14/17 MCL responses 4/13 FL responses Davids et al, EHA, 2014

36 Original Article Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma Constantine S. Tam, M.B., B.S., M.D., Mary Ann Anderson, M.B., B.S., Ph.D., Christiane Pott, M.D., Ph.D., Rishu Agarwal, M.B., B.S., Sasanka Handunnetti, M.B., B.S., Rodney J. Hicks, M.B., B.S., Kate Burbury, M.B., B.S., Gillian Turner, B.N., M.I.P.H., Juliana Di Iulio, Ph.D., Mathias Bressel, M.Sc., David Westerman, M.B., B.S., Stephen Lade, M.B., B.S., Martin Dreyling, M.D., Sarah-Jane Dawson, M.B., B.S., Ph.D., Mark A. Dawson, M.B., B.S., Ph.D., John F. Seymour, M.B., B.S., Ph.D., and Andrew W. Roberts, M.B., B.S., Ph.D. N Engl J Med Volume 378(13): March 29, 2018

37 Ibrutinib plus venetoclax in MCL: Study Schema 24 patients; 23 relapsed or refractory; most high-risk including MIPI score and TP53 mutations Tam CS et al. N Engl J Med 2018;378:

38 Kinetics of Response and Clearance of Minimal Residual Disease (MRD) Tam CS et al. N Engl J Med 2018;378:

39 MCL: Ibrutinib plus venetoclax n = 24 Progression-free survival Median follow-up 16 mo Complete response by PET/CT scan = 71% 3 non-responders Toxicity mostly grade 1-2 diarrhea, fatigue Grade 3-4: 33% neutropenia 12% diarrhea 4% bleeding 8% atrial fibrillation 8% tumor lysis Duration of Response Overall survival Tan et al, NEJM 2018 Tam CS et al. N Engl J Med 2018;378:

40 Phase I/Ib study of Ven and Ibr Major inclusion/exclusion Ibrutinib naïve not high risk for TLS Relapsed to 1 prior chemotherapy containing regimen Treatment Schema: 400mg Arms C, E, & F Venetoclax 20mg 50mg 100mg 100mg 200mg 200mg Arms A, B, & D Ibrutinib dosing per allocation Week 1 Week 2 Week 1 Week 2 Week 3+ Cycle 0 Cycle 1

41 Ibrutinib Combined With Venetoclax in R/R Mantle Cell Lymphoma (SYMPATICO) Initiated May 2017 Sponsor: Pharmacyclics Phase 3 multinational, randomized, double-blind study to compare the efficacy and safety of the combination of ibrutinib and venetoclax vs. ibrutinib and placebo in subjects with MCL R/R MCL, 1-5 prior treatments

42 Adherence and Oral Therapies in Lymphoma and CLL: A Lymphoma Research Foundation Workshop October 19, 2017

43 Program Goals Review epidemiology/forms nonadherence, methods of adherence assessment, and barriers to accurately measuring adherence Identify primary causes of nonadherence as well as related adherence interventions and tools Discuss the design and implementation of studies focused on adherence in lymphoma/cll

44 Joseph Greer, PhD, Mass. General Hospital

45 Background Pilot study of 90 patients with CML, metastatic NSCLC, RCC, BC Percentage of Patients with Greater than 90% Adherence to Oral Chemotherapy Adherence per MEMS Mean = 89.3% Less than 90% = 25.6% Predictors of better adherence: Improved symptom distress, mood, QOL, satisfaction with providers and treatment, and perceived burden to others Jacobs et al. J Oncol Pract, 2017

46 Treatment Schedules Are Complex Sun Mon Tues Wed Thur Fri Sat Week 1 Lenolidomid Lenolidomide Ixazomib Lenolidomide Dexamethason Lenolidomide Lenolidomide Lenolidomide Lenolidomide Week 2 Lenolidomid Lenolidomide Dexamethason Rest Rest Rest Rest Week 3 Rest Rest Ixazomib Lenolidomide Dexamethason Lenolidomide Lenolidomide Lenolidomide Lenolidomide Regimens are complex, almost always given in addition to other medications Adherence is inversely related to dosing complexity clinicians must realize that lack of adherence typically reflects the complexity of the regimen rather than willful or manipulative behavior from the patient. (2008 National Comprehensive Cancer Network Task Force Report on Oral Chemotherapy) 46

47 Wendy Nelson, PhD, NCI: RFA for Adherence to oral anticancer therapy 47

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51 Grant NIH Research Mechanisms Project R01 and NIH R21 Grant Exploratory/Development (R01) al Grant (R21) PA PA Supports discrete, specified, circumscribed research projects Most commonly used grant mechanism No specific dollar limit Advance permission required for >$500K direct costs in any year 3-5 years of funding Standard receipt dates Supports exploratory/developmental research projects May be used for pilot or feasibility studies Preliminary data not required Direct costs for the two-year project period may not exceed $275K 2 years of funding Standard receipt dates For more information: grants.nih.gov/grants/funding/funding_program.htm#rseries 51

52 Michael Mauro, MD, MSKCC 52

53 CML in the era of TKI therapeutics 53

54 Pharmacy Record Analysis of 4043 Patients Prescribed Imatinib Patient adherence with imatinib therapy estimated at 75% Only 41% of patients were more than 90% adherent 3,500 2,921 2,913 2,908 2,883 3,000 2,742 2,617 2,448 2,500 Patients 2,000 1,500 1,000 Dramatic decline in persistency Month 4: near 100% Month 5: 94% 2,269 2,126 1,997 1,866 1,671 1, Month 14: 23% Months Tsang, J-P, Rudychev I, Pescatore SL. J Clin Onc. 2006; 24:330s. Abs 6119.

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57 Microelectronic Monitoring System (MEMS 6 Trackcap) CML Study Records the time of opening the container Most reliable method of measuring adherence Marin study: patients told that adherence was measured by pill counts, not told about bottle cap electronic chip Marin D, et al. J Clin Oncol 2010; 28(14):

58 The Ideal: 100% adherence as recorded by MEMS Marin D, et al. J Clin Oncol 2010; 28(14):

59 The Reality: Catching up to empty the bottle, as recorded by MEMS Marin D, et al. J Clin Oncol 2010; 28(14):

60 The Reality: Poor adherence due to drug holiday, as recorded by MEMS Marin D, et al. J Clin Oncol 2010; 28(14):

61 The Reality: Poor adherence and Human Nature, as recorded by MEMS Marin D, et al. J Clin Oncol 2010; 28(14):

62 Likelihood of patients speaking up Sonali Smith, MD Table 2. Multivariable Models for Cumulative Incidence of 2 Failure Types: Disease Progression and Toxicity, Adjusted for Monotherapy Variable Progression Event Toxicity HR (95% CI) a P Value HR (95% CI) a P Value Age, 10-y increase NA NA 1.87 ( ) <.001 No. of prior treatments, 1 unit increase NA NA 1.09 ( ).054 BCL6 abnormality, yes vs no 2.70 ( ).01 NA NA Complex karyotype, yes vs no 4.47 ( ).007 NA NA q Patient age q Language barrier q Education barrier q Physician and/or nurse accessibility q Culture of reporting Maddocks JAMA Onc 2016

63 Challenges in capturing toxicity Subjectivity Communication and documentation Unpredictable timing of events The need to capture late effects is particularly relevant for chronic therapies

64 There s an app for that Factors influencing use of an app: Type of feedback given on reported ADR s How ADR reports are stored Security of the app Layout Operating systems Cost Falchook Advances in Radiation Oncology: April-June 2016; De Vries Drug Saf (2017) 40:

65 Capturing delayed toxicities requires vigilance Ibrutinib Early events: Petechiae Rash Diarrhea (mild) Late events: Hypertension Headaches Atrial fibrillation Peripheral edema Idelalisib Early events: Diarrhea (mild) Transaminase elevation Rash Late events: Colitis (severe) Pneumonitis Infection

66 Conclusions: Oral Anticancer Therapy New models to provide care for patients on oral anticancer therapy are needed Polypharmacy issues a concern, as are complex/multiagent treatment administration schedules There are no standardized methods for assessing adherence, and no standard definition of adherence and the ways in which it affects clinical outcomes Oral therapies may lead to financial burden, high copays and may contribute to poor adherence in setting of years of ongoing therapy Some toxicities of chronic oral therapies may not emerge until after years on treatment Williams ME, Friedberg JW. Editorial, ASCO Post, May 2018 Friedberg JW, Williams ME, White Paper online at lymphoma.org, Lymphoma Research Foundation