Top 10 Advances Impacting Clinical Practice in Hematologic Malignancies

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1 Top 10 Advances Impacting Clinical Practice in Hematologic Malignancies With updates from ASCO 2017 and ASH 2016 Edward A. Stadtmauer, MD Professor of Medicine Section Chief, Hematologic Malignancies Abramson Cancer Center Philadelphia, Pa Please note that some of the studies reported in this presentation were presented as an abstract and/or presented at a national conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

2 MYELOMA AND PLASMA CELL DISORDERS

3 Immunotherapy for MM: Targets and Tools Neri et al, Clin Can Res 2016

4 Phase 2 study of Pembrolizumab/pom/dex for RRMM Pts with R/R MM with 2 prior therapies including PI and IMiD (n = 48) Pembrolizumab 200 mg IV D1,14* Pomalidomide 4 mg PO D1-21 Dexamethasone 40 mg PO D1,7,14,21 28-day cycles until PD After 24 mos responding pts can continue pomalidomide/ dexamethasone until PD *First 6 pts treated on D1 only. 20 mg for pts older than 70 yrs of age. Median 3 priors, 73% double-refractory, all pom-naïve Median 8 cycles (range 3-23) Tox: fatigue, cytopenias, dyspnea, hyperglycemia 11% d/c 2/2 toxicity; 1 infectious death Autoimmune: pneumonitis (12%), hypothyroid (10%), hepatitis (6%) ORR 65% ( VGPR 29%) (n=45 evaluable) Median PFS 17.4 mos, OS NR at 18 mos Badros et al, ASH 2016, #490

5 Anti-BCMA antibody-drug conjugate

6 Phase 1 study of GSK in RRMM Dose-escalation ( mg/kg) 60 min infusion, q3 weeks up to 16 cycles Pre-med with steroid eye drops (corneal toxicity) Cohen et al, ASH 2016, #1148

7 Phase 1 study of GSK in RRMM Cohen et al, ASH 2016, #1148

8 Phase 1 study of GSK in RRMM Expansion cohort ongoing Cohen et al, ASH 2016, #1148

9 CART-BCMA for myeloma: Study design Cohort x 10 8 CAR+ T cells (n=3-6) Cohort 2 Cytox 1.5 g/m x 10 7 CAR+ T cells (n=3-6) Cohort 3 Cytox 1.5 g/m x 10 8 CAR+ T cells (n=3-6) Up to n=9 Up to n=9 Up to n=9 Manufacturing

10 Patient characteristics Cohort 1 (n=9) Cohen et al, ASH 2016, #1147 Characteristic Median (range) or % Age 57 (44 70) Gender 67% male; 33% female Isotype IgG (33%), IgA (44%), LC (22%) Prior lines of therapy 9 (4-11) Lenalidomide 100% (refractory: 78%) Bortezomib 100% (refr: 89%) Pomalidomide 100% (refr: 89%) Carfilzomib 100% (refr: 89%) Autologous SCT 78% Cyclophosphamide 100% (refr: 67%) Daratumumab 44% (refr: 44%) High-risk genetics -17p or TP53 mutation Anti-PD1 33% (refr: 33%) 100% 67% Extramedullary dz 33% % BM plasma cells 80 (15 95) Day 0 absolute CD3 258/µL ( )

11 Safety (n=9) Cytokine release syndrome in 8/9 (89%) Grade 1 (n=1); Grade 2 (n=4); Grade 3 (n=2); Grade 4 (n=1) 4/9 received tocilizumab Median hospital stay = 9 days (range 3 40) Dose-limiting toxicity (pt. 03): Grade 4 PRES (posterior reversible encephalopathy syndrome) Recurrent seizures, obtundation MRI brain: diffuse enhancement w/ swelling and sulcal effacement. Rapid peripheral CART expansion Solumedrol 1 g/d x 3 Cytoxan 1.5 g/m2 day 17 Rapid improvement, resolution of MRI changes and neuro deficits Garfall et al, ASH 2016, #5702 Cohen et al, ASH 2016, #1147

12 CART-BCMA for MM: Cohort 1 (CART cells alone) 4/9 (44%) with response, 1 with scr>18 months Associated with CART expansion, sbcma Pt 01 Pt 03 Enrollment ongoing in cohorts using Cytoxan conditioning Cohen et al, ASH 2016, #1147 Pre-tx Day 42

13 bb2121 CART-BCMA cells Berdeja et al, EORTC-NCI-AACR Symposium 2016, #14LBA; ASCO 2017 Abstract 3010/PB105

14 Comparison of CART-BCMA trials NCI Penn (cohort 1) Bluebird Sites Single Single Multi-center scfv Murine Human Murine Vector Gamma-retroviral Lentiviral Lentiviral Domains CD3/CD28 CD3/41BB CD3/41BB BCMA+ required Yes (IHC) (52/85 (62%) +) No Yes (??) Dosing 0.3 9x10 6 /kg 1 day 5 x days x day Conditioning Flu/Cy - Flu/Cy Med # priors 7* 9 6 Responses (Longest) 4/12 (4.5+ mos) 4/9 (18+ mos) 7/9 (8+ mos) *includes XRT Ali et al, Blood 2016; Cohen et al, ASH 2016, #1147; Lin et al, EORTC-NCI-AACR Symposium 2016

15 Daratumumab Dara/Len/dex vs Len/dex Dara/Btz/dex vs Btz/dex Dimopoulos MA et al. N Engl J Med 2016;375: Palumbo A et al. N Engl J Med 2016;375:

16 Daratumumab: Infusion reactions 38% (1 st infusion: 36%, 2 nd : 2%, 3 rd +: 3%) Mostly grade 1-2 Grade 3: bronchospasm, dyspnea, chills/crs, hypertension Infusion reaction prophylaxis Monteleukast 10 mg qhs, days -1, 0, +1, +2 (x 4 weeks) INFUSION: Volume 1000 ml 500 ml 500 ml Methylprednisolone 100 mg IV Acetaminophen 975 mg PO Diphenhydramine 25 mg IV PRN: famotidine 20 mg IV, lorazepam 1 mg IV Start 50 ml/h 50 ml/h 100 ml/h increase to 200 ml/h at 50 ml/h intervals with reaction: pause, restart at 50% of previous rate Premedication Methylprednisolone 100 mg (1st and 2nd) or 60 mg (3rd +) Acetaminophen mg Dexamethasone 4 mg PO, days +1, +2 Diphenhydramine mg Post-medication Methylprednisolone 20 mg on days 2 and 3 of each infusion COPD/asthma: inhaled corticosteroid days 0, +1 Zoster prophylaxis Voorhees, ASH 2015, Abstract 1829.

17 Subcutaneous daratumumab Slide credit: clinicaloptions.com Phase Ib trial of SC daratumumab + recombinant human hyaluronidase enzyme (rhuph20) 1200 mg (20 min) or 1800 mg (30 min) Pre/postinfusion acetaminophen, diphenhydramine, montelukast, and methylprednisolone *. ORR 25% (1200 mg) and 38% (1800 mg) Infusion-Related Reaction, % 1200 mg (n = 8) 1800 mg (n = 45) Overall Chills 13 9 Pyrexia 0 9 Pruritus 0 4 Dyspnea 13 0 Flushing 0 2 Hypertension 0 2 Hypotension 0 2 Nausea 0 2 Next stage of study will randomize patients to recommended SC dose vs daratumumab IV 16 mg/kg Usmani SZ, et al. ASH Abstract 1149.

18 BMT CTN 0702 Stem Cell Transplantation for Multiple Myeloma Incorporating Novel Agents: SCHEMA Lenalidomide * Maintenance N=750 pts (250 in each arm) N=257 * Register and Randomize *Bortezomib 1.3mg/m2 days 1, 4, 8,11 Lenalidomide 15mg days 1-15 Dexamethasone 40mg days 1, 8, 15 Every 21 days MEL VRD x 4* 200mg/m 2 N=254 N=247 MEL 200mg/m 2 Lenalidomide Maintenance** Lenalidomide Maintenance** **Lenalidomide x 3years : 10mg/d for 3 cycles, then 15 mg/d Amendment in 2014 changed Lenalidomide maintenance until disease progression after report of CALGB

19 High-Risk vs Standard Risk Stratification High-risk multiple myeloma High beta-2 microglobulin (> 5.5mg/L) High-Risk cytogenetic abnormalities: t(4;14), t(14;20), t(14;16), deletion (17p) detected by FISH or standard cytogenetics Deletion 13 detected by standard cytogenetics only Standard-Risk multiple myeloma Patients without cytogenetic analysis available Beta-2 microglobulin 5.5mg/L Deletion 13 detected by FISH only 19

20 BMT CTN 0702 Survival Curves

21 Patient Characteristics

22 BMT CTN 0702 (STAMiNA) Summary Largest randomized comparison of post transplant approaches in myeloma in the United States Demographics well balanced among auto/auto, auto/rvd, auto/maintenance At 38 months follow-up no difference in OS: Auto/auto 82%, auto/rvd 85.7%, auto/maint 83.4% At 38 months follow-up no difference in PFS: Auto/auto 56.5%, auto/rvd 56.7%, auto/maint 52.2% (high-risk worse than standard risk, but no difference by treatment arm) Cumulative incidence of first secondary malignancy in the first 38 months similar for all 3 arms 5.9% in the Auto/Auto 6.0% in the Auto/RVD in the Auto/Maint 22

23 LYMPHOMA

24 No difference in 3-yr EFS or 3-yr OS EFS R-CHOP 81% vs DA-EPOCH-R 79% OS R-CHOP 85% vs DA-EPOCH-R 85% No clinical subgroup identified based on age or IPI that appears to benefit from DA-EPOCH-R Inadequate numbers to comment on PMBCL (n=28) Double expresser, double hit analysis pending DA-EPOCH-R associated with modest increase in Gr-3-4 toxicities (cytopenias, F/N, neuropathy) Pending conclusions: multiple potential PET, pharmacogenomic pathology, and molecular correlates Wilson et al. ASH Abstract 469.

25 In GOYA, G-CHOP did not improve PFS compared with R-CHOP in previously untreated pts with DLBCL AEs were consistent with the known safety profile of G Grade 3 5 AEs and SAEs were more common in the G-CHOP arm Further analyses of GOYA data will inform and shape the direction of future research activities in DLBCL R-CHOP remains the standard of care in this setting Vitolo et al. ASH Abstract 470.

26 Key eligibility criteria Aggressive NHL: DLBCL, PMBCL, TFL Chemotherapy-refractory disease: no response to last chemotherapy or relapse 12 mo ASCT Prior anti-cd20 mab and anthracycline ECOG PS 0-1 Phase 1 Phase 2 Refractory DLBCL/PMBCL/TFL (cohort of n=6) Cohort 1 Refractory DLBCL (n=72) Cohort 2 Refractory PMBCL/TFL (n=20) Primary endpoint: ORR Secondary endpoints: DOR, OS, safety, levels of CAR T and cytokines Conditioning chemotherapy: 500 mg/m 2 Cy, 30mg/m 2 Flu, x3 days Dosed with 2 x10 6 /kg KTE-C19 Pre-specified efficacy interim analysis Phase 2 cohort 1 (n=50 with 3 months of follow-up) Neelapu et al. ASH Abstract LBA-6.

27 Response at 1 or 3 month follow-up, % 1 month a (n=73) DLBCL PMBCL/TFL Total 3 months (n=51) 1 month a (n=20) 3 months (n=11) 1 month a (n=93) 3 months (n=62) ORR b CR a Does not include responses after 1 month b *P< (exact binomial test comparing observed ORR in DLBCL to a historical control assumption of 20%) Responses were consistent in key subgroups: 75% (n=9/12) CR relapsed post-asct 47% (n=23/49) CR refractory to 2 nd + line Consistent treatment effects across key covariates Peak CAR T cell expansion observed between 7-14 days Ongoing responses and grade 3 neurologic events associated with CAR T cell expansion, (P = and 0.02, respectively) Neelapu et al. ASH Abstract LBA-6.

28 Adverse Event, n (%) DLBCL (n=73) TFL/PMB CL (n=20) All Patients (N=93) Grade 3 adverse event 68 (93) 18 (90) 86 (92) Grade 3 Cytokine Release Syndrome 10 (14) 2 (10) 12 (13) Grade 3 neurologic events (NE) 18 (25) 9 (45) 27 (29) Fatal events excluding PD 2 of 3 KTE-C19-related Grade 3 Adverse Event in 15% Patients, n (%)* Neutropenia/Neutrophil count decreased Neelapu et al. ASH Abstract LBA-6. 1 (1) 2 (10) 3 (3) N=93 (%) 59 (63) Anemia 39 (42) Leukopenia/WBC count decreased 37 (40) Febrile neutropenia 27 (29) Thrombocytopenia 24 (26) Encephalopathy 18 (19) Hypophosphatemia 16 (17) Lymphocyte count decreased 16 (17) CRS and NE were generally reversible All CRS events resolved except 1 cardiac arrest (cohort 2) All NE resolved except 3 ongoing at data-cut (Gr 1 memory impairment, Gr 1 tremor, Gr 2 tremor) 1 patient died due to PD with NE ongoing Grade 5 events: 3 patients (3%) KTE-C19-related: HLH (Cohort 1) and cardiac arrest (Cohort 2) in the setting of CRS KTE-C19-unrelated: pulmonary embolism (Cohort 2)

29 At this pre-specified interim analysis, ZUMA-1 met primary endpoint with 76% ORR and 47% CR (p<0.0001) First pivotal, multicenter study of anti-cd19 CAR T cells in refractory aggressive NHL KTE-C19 induced nearly 6-fold higher CR rate compared with historical outcomes, with 39% durable CR at 3 months Responses observed across broad range of covariates CRS and neurologic events were manageable Grade 5 adverse event rate was 3% Peak CAR T cell levels were associated with ongoing responses and grade 3 neurologic events 99% manufacturing success rate with 17 day turnaround time AE management successfully implemented across 22 sites, most with no prior CAR T therapy experience Neelapu et al. ASH Abstract LBA-6.

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32 Five-Year Experience With Single-Agent Ibrutinib in Patients With Previously Untreated and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia Susan O Brien, MD 1,2, Richard R. Furman, MD 3, Steven Coutre, MD 4, Ian W. Flinn, MD, PhD 5, Jan Burger, MD, PhD 1, Kristie Blum, MD 6, Jeff Sharman, MD 7, William Wierda MD, PhD 1, Jeffrey Jones MD, MPH 6, Weiqiang Zhao, MD, PhD 6, Nyla A. Heerema, PhD 6, Amy J. Johnson, PhD 6, Ying Luan, PhD 8, Danelle F. James, MD, MAS 8, Alvina D. Chu, MD 8, John C. Byrd, MD 6 1 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX; 2 University of California, Irvine, CA; 3 Department of Medicine, Weill Cornell Medical College, New York, NY; 4 Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA; 5 Sarah Cannon Research Institute, Nashville, TN; 6 The Ohio State University, Columbus, OH; 7 Willamette Valley Cancer Institute and Research Center, Springfield, OR; 8 Pharmacyclics, LLC, an AbbVie Company, Sunnyvale, CA.

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39 Leukemia

40 CPX nm bilamellar liposomes 5:1 molar ratio of cytarabine to daunorubicin 1 unit = 1.0 mg cytarabine plus 0.44 mg daunorubicin Lancet J et al. J Clin Oncol. 2016;34:(suppl; abstr 7000).

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42 Response rate and early mortality favor CPX-351 over 7&3 in older patients age >60 CPX-351 (n=153) 7 & 3 (n=156) Lancet JE et al. Blood. 2016;128:906a.

43 Overall survival and post-hsct survival improved by CPX-351 in Secondary AML Lancet JE et al. J Clin Oncol. 2016;34:(suppl; abstr 7000); Lancet JE et al. Blood. 2016;128:906a.

44 Outcomes of patients receiving imatinib as initial therapy in CP-CML Cortes and Kantarjian Hematology 2016:

45 TIDEL-II, ASH 2016, Abst 939 Upfront imatinib with selective early switching to nilotinib leads to excellent achievement of deep molecular response in chronic phase CML: 5 year (final) analysis of the TIDEL II study David T Yeung et al on behalf of ALLG

46 Two-cohort Imatinib->Nilotinib Treatment Schema Cohort 1, n=105 Trough IM <1000ng/mL BCR-ABL 10% IS BCR-ABL 1% IS BCR-ABL 0.1% IS IM 800 IM 800 IM 800 Imatinib 600mg QD Nilotinib 400mg BID IM 800 ELN Targets d22 3mo 6mo 12mo 24mo Cohort 2, n=105, directly to nilotinib Slide adapted from E. Hexner, ASH Update 2017

47 TIDEL-II as a frontline strategy DASISION [1] ENESTnd [2] TIDEL-II IM 400 DAS IM 400 NIL IM->NIL OS, 5yrs 90% 91% 92% 94% 92% BC 7% 5% 8% 4% 4% EMR failure 36% 16% 33% 11% 12% 5yr MMR 64% 76% 60% 77% 86% 5yr MR4.5 33% 42% 31% 54% 60% Withdrawn 37% 39% 50% 40% 37% 1. Cortes et al. JCO 2016;34: Hochhaus et al. Leukemia. 2016;30: Slide courtesy of E.Hexner, ASH Update 2017