New Treatments and Combinations for Relapsed Chronic Lymphocytic Leukemia (CLL) Susan O Brien UC Irvine Health

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1 New Treatments and Combinations for Relapsed Chronic Lymphocytic Leukemia (CLL) Susan O Brien UC Irvine Health

2 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

3 Best Response TN (n=31) R/R (n=101) Total (N=132) 87% 89% 89% CR PR PR-L Median DOR, months (range) Median follow-up, months (range) NR, not reached. O Brien SM, et al. Blood. 2016;128: Abstract 233. NR (0.0+ to 65.5+) 56.8 (0.0+ to 65.5+) NR (0.0+ to 65.5+) 62 (1 67) 49 (1+ 67) 56 (1+ 67)

4 Survival Outcomes: Overall Population Progression-Free Survival Overall Survival Median PFS 5-year PFS TN (n=31) NR 92% R/R (n=101) 52 mo 43% NR, not reached. O Brien SM, et al. Blood. 2016;128: Abstract 233. Median OS 5-year OS TN (n=31) NR 92% R/R (n=101) NR 57%

5 Survival Outcomes by Chromosomal Abnormalities Detected by FISH in R/R Patients* Progression-Free Survival Overall Survival Median PFS 5-year PFS Del17p (n=34) 26 mo 19% Del11q (n=28) 55 mo 33% Trisomy 12 (n=5) NR 80% Del13q (n=13) NR 91% No abnormality** (n=16) NR 66% Median OS 5-year OS Del17p (n=34) 57 mo 32% Del11q (n=28) NR 61% Trisomy 12 (n=5) NR 80% Del13q (n=13) NR 91% No abnormality** (n=16) NR 83% *Only 2 patients in the TN group showed PD or death. Subgroup analyses, therefore, focused on the R/R population. **No del17p, del11q, del13q, or trisomy 12; in hierarchical order for del17p, and then del11q NR, not reached. O Brien SM, et al. Blood. 2016;128: Abstract 233.

6 Venetoclax Monotherapy for Patients with Chronic Lymphocytic Leukemia (CLL) who Relapsed After or Were Refractory to Ibrutinib or Idelalisib Jeffrey Jones, 1 Michael Y. Choi, 2 Anthony R. Mato, 3 Richard R. Furman, 4 Matthew S. Davids, 5 Leonard Heffner, 6 Bruce D. Cheson, 7 Nicole Lamanna, 8 Paul M. Barr, 9 Herbert Eradat, 10 Ahmad Halwani, 11 Brenda Chyla, 12 Maria Verdugo, 12 Rod A. Humerickhouse, 12 Jalaja Potluri, 12 William G. Wierda, 13 Steven Coutre 14 American Society of Hematology San Diego, California 5 December 2016

7 Venetoclax Dosing Schedule and TLS Mitigation To mitigate TLS risk, patients received prophylaxis with uric acid lowering agents and hydration starting at least 72 hours before first venetoclax dose Patients with high tumor burden were hospitalized for first dose at 20 and 50 mg and received IV hydration and rasburicase Laboratory values were monitored at first dose and each subsequent dose increase High tumor burden: any lymph node 10 cm; or both lymph node 5 cm and ALC 25x10 9 /L Jones J, et al. Blood. 2016;128: Abstract

8 Patient Characteristics Arm A Arm B n=43 n=21 Age, median (range), years 66 (48 80) 68 (56 85) Unmutated IGVH,* n/n (%) 25/29 (86) 11/13 (85) del(17)(p13.1),* n/n (%) 21/43 (49) 2/21 (10) Baseline laboratory values, median (range) CrCl, ml/min Hemoglobin, g/dl Platelet count, x10 9 /L Neutrophil count, x10 9 /L Lymphocyte count, x10 9 /L 83 (54 119) 11.2 ( ) 117 (20 446) 3.5 (0 24) 19 (.2 263) Bulky nodal disease, n (%) 5 cm 10 cm 75 (44 140) 12.2 ( ) 115 (30 439) 2.4 (0 49) 14 (.3 407) 15 (35) 7 (16) 11 (52) 5 (24) Prior therapies, median (range) 4 (1 12) 3 (1 11) Prior ibrutinib, n (%) Months on ibrutinib, median (range) Refractory, n (%) 43 (100) 17 (1 56) 39 (91) 5 (24) 6 (2 11) 2 (10) Prior idelalisib, n (%) Months on idelalisib, median (range) Refractory, n (%) *Site reported data. 2 received only frontline ibrutinib; 2 received only frontline idelalisib. Jones J, et al. Blood. 2016;128: Abstract (9) 10 (2 31) 2 (5) 21 (100) 8 (1 27) 14 (67)

9 Best response, n (%) Efficacy Arm A n=43 Arm B n=21 Assessed by Assessed by IRC Investigator IRC Investigator ORR 30 (70) 29 (67) 13 (62) 12 (57) CR/CRi 0/1 (2) 2 (5)/1 (2) 0/0 2 (10)/1 (5) npr 0 2 (5) 0 0 PR 29 (67) 24 (56) 13 (62) 9 (43) Non-responder* SD PD D/C 13 (30) 14 (23) 9 (21) 1 (2) 4 (9) 8 (38) 9 (43) 8 (38) 1 (5) 0 *Non-responder category for IRC includes both SD or PD, which were not identified as separate categories per IRC. CLL progression and discontinued due to progression. D/C, patient discontinued the study prior to assessment. Jones J, et al. Blood. 2016;128: Abstract 637.

10 Efficacy Per Independent Review Median DoR, PFS, and OS had not been reached after 11.8 months of follow up Estimated 12 month PFS for all patients: 80% (95% CI: 67%, 89%) Patients with Response (%) Duration of Response Arm A (R/R ibrutinib) A rm B (R /R idelalisib) A ll p atients Progression-free survival (%) Progression-Free Survival Arm A (R/R ibrutinib) A rm B (R /R idelalisib) A ll p atients Months since first dose Months since first dose No. at risk Jones J, et al. Blood. 2016;128: Abstract Data as of 10June2016

11 Minimal Residual Disease in Peripheral Blood MRD-positive MRD-negative CRi PR Non-responder by IRC % CLL Cells A rm A (R /R ibrutinib) % CLL Cells A rm B (R /R idelalisib) * # Patients Patients *Patient had persistent splenomegaly and thrombocytopenia; categorized as stable disease by investigator. # Also had confirmed bone marrow MRD-negative assessment. 14/31 (45%) patient samples have demonstrated MRD-negative peripheral blood between Weeks patients demonstrating sustained MRD negative status in blood had subsequent marrow evaluations; 1 patient was MRD negative in bone marrow Jones J, et al. Blood. 2016;128: Abstract 637. Data as of 10June

12 Outcomes of CLL Patients Treated With Sequential Kinase Inhibitor Therapy: A Real World Experience Mato AR, Nabhan C, Barr PM, Ujjani CS, Hill BT, Lamanna N, Skarbnik AP, Howlett C, Pu JJ, Sehgal AR, Strelec LE, Vandegrift A, Fitzpatrick DM, Zent CS, Feldman T, Goy A, Claxton DF, Bachow SH, Kaur G, Svoboda J, Nasta SD, Porter D, Landsburg DJ, Schuster SJ1, Cheson BD, Kiselev P, Evens AM Mato et al. Blood Nov 3;128(18): Epub 2016 Sep 6;

13 Outcomes with Second Kinase Inhibitor Therapy in CLL PFS for alternate KI. (A) PFS from start of alternate KI (ibrutinib idelalisib, idelalisib ibrutinib). (B) PFS from start of alternate KI stratified by reason for discontinuation (CLL progression vs KI intolerance). Mato AR, et al. Blood. 2016;128(18):

14 Phase 1b Results of a Phase 1b/2 Study of Obinutuzmab, Ibrutinib, and Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) Jeffrey A. Jones, MD, MPH 1 ; Jennifer Woyach, MD 1 ; Farrukh T. Awan, MD 1 ; Kami J. Maddocks, MD 1 ; Thomas Whitlow, BA 2 ; Amy S Ruppert, MAS 1 ; and John C. Byrd, ASH 2016

15 Jones JA, et al. Blood. 2016;128: Abstract 639. Treatment Schema

16 Cycle 9 Treatment Response Jones JA, et al. Blood. 2016;128: Abstract 639.

17 Safety Event, n (%) All Patients N=64 Any grade AE 64 (100) Common all-grade AEs ( 20% patients) Neutropenia Thrombocytopenia Diarrhea Nausea Anemia Fatigue Decreased WBC Hyperphosphatemia 37 (58) 28 (44) 27 (42) 26 (41) 23 (36) 20 (31) 14 (22) 14 (22) Event, n (%) All Patients N=64 Grade 3/4 AEs 53 (83) Common grade 3/4 AEs ( 10% patients) Neutropenia Thrombocytopenia Anemia Decreased WBC Febrile neutropenia Pneumonia 29 (45) 18 (28) 14 (22) 8 (13) 7 (11) 7 (11) Serious AEs 34 (53) Febrile neutropenia Pneumonia Multi-organ failure Septic shock Increased potassium 6 (9) 5 (8) 2 (3) 2 (3) 2 (3) No clinical TLS was observed; 1 patient with high tumor burden met Howard criteria for laboratory TLS Jones JA, et al. Blood. 2016;128: Abstract 639. Data as of 10June

18 Conclusions Obinutuzumab, ibrutinib, and venetoclax can be safely administered at each single agent dose Dose-limiting toxicity was not observed Adverse events were manageable and largely consistent with those reported in studies of the single-agents Hematologic toxicity was common but manageable Grade 3/4 non-hematologic toxicity was uncommonly observed Responses were recorded at Cycle 9 in all patients assessed MRD negativity at cycle 9 was achieved in PB for 7 of 10 and in BM for 4 of 10 patients assessed Accrual is nearly completed to parallel phase 2 cohorts of relapsed/refractory (n=25) and treatment-naive (n=25) patients. Jones JA, et al. Blood. 2016;128: Abstract 639.

19 496 Results of the Safety Run-In Phase of CLL14 (BO25323): A Prospective, Open-Label, Multicenter Randomized Phase-III Trial to Compare the Efficacy and Safety of Obinutuzumab and Venetoclax (GDC-0199/ABT-199) with Obinutuzumab and Chlorambucil in Patients with Previously Untreated CLL and Coexisting Medical Conditions Kirsten Fischer, MD, Anna-Maria Fink, MD, Helen Bishop, Mark Dixon, Jasmin Bahlo, Michael Y. Choi, MD, Robert Weinkove, MD, PhD, Sue Robinson, MD, Martin Dreyling, MD, PhD, Till Seiler, MD, Stephen Opat, MD, Carolyn Owen, MD, Javier Lopez Sr., MD, PhD, Nadine Kutsch, MD, Eugen Tausch, MD, Matthias Ritgen, MD, Rod Humerickhouse, MD, Kathryn Humphrey, Michael K. Wenger, MD, Valentin Goede, MD, Barbara Eichhorst, MD, Clemens-Martin Wendtner, MD, Stephan Stilgenbauer, MD, Thomas J. Kipps, MD, PhD and Michael Hallek, MD ASH 2016 Fischer et al. Blood May 11;129(19):

20 Design Patients with untreated active CLL & with coexisting medical conditions* Safety Run-In Phase: Obinutuzumab + Venetoclax Independent Data Monitoring Commitee (idmc) Obinutuzumab + Chlorambucil 6 x Obinutuzumab + Chlorambucil + 6 x Chlorambucil Obinutuzumab + Venetoclax 6 x Obinutuzumab + Venetoclax + 6 x Venetoclax Follow-up Phase *CIRS > 6 and/ or CrCl < 70mL/min Fischer K, et al. Blood. 2017;129(19):

21 Stopping Criteria One treatment-related death One grade 4 adverse event related to a clinical tumor lysis syndrome despite protocolspecified prophylaxis Fischer K, et al. Blood. 2017;129(19):

22 Treatment Schedule: 12 cycles Obinutuzumab (iv infusion) 100 mg day 1, 900 mg day 2, 1000 mg day 8, day 15 of course 1, 1000 mg courses 2-6, day 1 Venetoclax (oral tablet) 20 mg daily during course 1, day mg daily during course 2, day mg daily during course 2, day mg daily during course 2, day mg daily during course 2, day mg daily courses 3-12, day 1-28 *Venetoclax Ramp-up during course 1 and 2 Fischer K, et al. Blood. 2017;129(19):

23 Patient Characteristics N=13 Median age 75 years (59-88) Binet stage A 15% B 23% C 62% Median CIRS score 8 (6-14) Median CreaClearance 58 ml/min (30-108) TLS risk category Low 0% Medium 62% High 39% Fischer K, et al. Blood. 2017;129(19):

24 Grade 3-4 Adverse Events N=13 AE Term Percentage Neutropenia 58% IRR 8% Syncope 17% Thrombocytopenia 17% TLS 17% Febrile Neutropenia 25% Bradycardia 8% Hyperglycaemia 8% Influenza 8% Leukopenia 8% Pyrexia 8% Respiratory Tract Infection 3% Transaminases Increased 8% Fischer K, et al. Blood. 2017;129(19):

25 Overall Response Rate N=12 At Month 15 ORR 100% CR 58% PR+ 42% Fischer K, et al. Blood. 2017;129(19):

26 N=11 Minimal Residual Disease At Month 15 MRD Level PB BM Negative (< 10-4 ) 11/12 5/7 Intermediate ( 10-4 and < 10-2 ) 1/12 2/7 Fischer K, et al. Blood. 2017;129(19):

27 Summary Run-in phase None of the protocol defined stopping criteria were met Initiating treatment with obinutuzumab followed by venetoclax appears safeolerable in this population The treatment induced substantial responses with a high number of MRD negative responses The main phase completed recruitment in August 2016 after 432 patients had been randomized Fischer K, et al. Blood. 2017;129(19):

28 Tolerability and activity of chemo-free triplet combination of umbralisib (TGR-1202), ublituximab, and ibrutinib in patients with advanced CLL and NHL Loretta Nastoupil, MD 1, Matthew A. Lunning, DO 2, Julie M. Vose, MD 2, Marshall T. Schreeder, MD 3, Tanya Siddiqi, MD 4, Christopher R. Flowers, MD 5, Jonathon B. Cohen, MD 5, Jan A. Burger, MD 1, William G. Wierda, MD 1, Susan O Brien, MD 6, Peter Sportelli 7, Hari P. Miskin, MS 7, Michelle A. Purdom, RN, PhD 7, Michael S. Weiss 7 and Nathan H. Fowler, MD 1 Presented at the 14 th International Conference on Malignant Lymphoma Lugano, Switzerland June 14 17, 2017

29 Ublituximab Single agent activity observed in rituximab refractory patients 1 90 minute infusion times

30 Umbralisib (TGR-1202) Next generation PI3Kδ inhibitor, with a unique structure and improved tolerability Umbralisib (TGR-1202) Idelalisib (GS-1101) Duvelisib (IPI-145) F O F O Cl O F N N O N N N N N NH N NH H 2 N N N HN N N HN N O F Delta Delta Delta/Gamma Burris HA, et al. J Clin Oncol. 2015;34(suppl): Abstract QD BID BID

31 Study Design Both ibrutinib and TGR-1202 were administered QD starting on Day 1 Efficacy assessed at Week 8 and every 12 weeks thereafter After Month 12, all patients remain on TGR-1202 and ibrutinib oncedaily Nastoupil L, et al. Presented at: the 14 th International Conference on Malignant Lymphoma. June 14-17, Lugano, Switzerland.

32 Demographics Evaluable for Safety (n) 38 Evaluable for Efficacy (n) 36 Median Age, years (range) 65 (32 85) Male/Female 29/9 Histology CLL/SLL 20 DLBCL 6 FL 6 MCL 4 MZL 2 ECOG, 0/1/2 14/21/3 Prior Therapy Regimens, median (range) 3 (0 6) Patients with 3 Prior Therapies, n (%) 21 (55%) Refractory to Prior Therapy, n (%) 13 (34%) Refractory to Rituximab, n (%) 15 (39%) 2 patients discontinued prior to first efficacy assessment (1 Pneumonia, 1 Investigator Discretion) 3 CLL patients were treatment naïve, all other patients were relapsed or refractory to prior therapy Nastoupil L, et al. Presented at: the 14 th International Conference on Malignant Lymphoma. June 14-17, Lugano, Switzerland.

33 Safety Adverse Event All Grades Grade 3/4 N % N % Diarrhea 18 47% 1 3% Fatigue 18 47% - - Dizziness 14 37% 1 3% Insomnia 13 34% - - Nausea 13 34% - - Neutropenia 12 32% 7 18% Cough 12 32% - - Infusion related reaction 12 32% - - Thrombocytopenia 11 29% 3 8% Pyrexia 11 29% 1 3% Rash 11 29% 1 3% Anemia 10 26% 1 3% Sinusitis 9 24% - - Dyspnea 8 21% 1 3% Stomatitis 8 21% 1 3% 1 DLT (reactivated varicella zoster) occurred CLL cohort level 1. No other DLT s were observed. Diarrhea majority Gr. 1 (32%) and Gr. 2 (13%), with no Gr. 4 event reported. Pneumonia (11% Gr. 3/4) and neutropenia were the only Gr. 3/4 AE s in >10% of patients Two patients discontinued due to an AE (sepsis and pneumonia) Median time on study 11.1 months (range months) Nastoupil L, et al. Presented at: the 14 th International Conference on Malignant Lymphoma. June 14-17, Lugano, Switzerland.

34 Efficacy: Overall Response Rate Type Pts CR PR ORR SD PD (n) (n) (n) n (%) (n) (n) CLL/SLL (100%) - - MZL (100%) - - MCL (100%) - - FL (80%) 1 - DLBCL (17%) - 5 Total (83%) 1 5 CLL CLL: 4/6 CR s pending bone marrow confirmation 8/16 (50%) had 17p and/or 11q deletion All 3 treatment naïve patients achieved a PR 3 had a prior BTK and/or PI3Kδ inhibitor, including one patient refractory to both idelalisib and ibrutinib (ongoing CR, 1.5+ years) FL patients were heavily pretreated including 2 with prior ASCT, 1 refractory to prior ibrutinib, and 1 with 5 prior lines of rituximab based therapy DLBCL Median of 4 prior therapies 4/6 were of non-gcb subtype, including the sole responder Nastoupil L, et al. Presented at: the 14 th International Conference on Malignant Lymphoma. June 14-17, Lugano, Switzerland.

35 Conclusions Ibrutinib produces very durable remissions in both relapsed and frontline patients. Venetoclax is the treatment of choice in patients failing a B- cell receptor inhibitor Novel combinations producing very exciting results with high degree of MRD negativity Ibrutinib, venetoclax and obinutuzumab, MRD negativity in relapse: 7/10 in PB, 4/10 in BM at cycle 9 of 14 Ventetoclax and obinutuzumab, MRD negativity in frontline at 15 mos ( EOT): 11/12 in PB, 5/7 in BM Umbralisib ( TGR-1202) is PI3K inhibitor with better safety profile. Combination with ublituximab ( anti CD20) and ibrutinib in relapsed CLL: 19/19 responses