Initial Therapy. Objectives. What s New in CLL?

Transcription

1 What s New in CLL? Jennifer A. Woyach MD Associate Professor of Medicine The Ohio State University The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Objectives To discuss data presented at ASH 2016 in the following areas of CLL: Initial therapy Relapsed disease Post-ibrutinib Richter s transformation 2 Initial Therapy 3 1

2 Early achievement of MRD-negativity in IGHV-mutated (IGHV-M) Patients Portends Highly Favorable Outcomes after First-Line Treatment of CLL with FCR. Serial Monitoring for MRD in Blood Predicts Clinical Progression. Philip A. Thompson, Paolo Strati, Jeff Jorgensen, Michael J. Keating, Susan M. O Brien, Alessandra Ferrajoli, Jan A. Burger, Stefan Faderl, Zeev Estrov, Nitin Jain, Tapan M. Kadia, Gautam Borthakur, Courtney DiNardo, Naval Daver, Elias Jabbour, and William G. Wierda. 4 Early MRD negativity with FCR MRD negativity following CIT is associated with superior PFS/OS 5 MRD-negative status after 3 courses is associated with superior PFS 2

3 IGVH mutated patients who achieve MRD negativity with 3 cycles may not benefit from additional FCR 7 Abstract: Updated Efficacy and Safety From the Phase 3 RESONATE-2 Study: Ibrutinib as First-Line Treatment Option in Patients 65 Years and Older With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Paul Barr, MD 1, Tadeusz Robak, MD 2, Carolyn Owen, MD 3, Alessandra Tedeschi, MD 4, Osnat Bairey, MD 5, Nancy Bartlett, MD 6, Jan Burger, MD, PhD 7, Peter Hillmen, MBChB, PhD 8, Steven Coutre, MD 9, Stephen Devereux, PhD, FRCP, FRCPath 10, Sebastian Grosicki, MD, PhD 11, Helen McCarthy, MBBS, PhD 12, Jianyong Li, MD 13, David Simpson, MBChB, FRACP, FRCPA 14, Fritz Offner, MD 15, Carol Moreno, MD 16, Cathy Zhou, MS 17, Lori Styles, MD 17, Danelle James, MD, MAS 17, Thomas J. Kipps, MD, PhD 18, and Paolo Ghia, MD, PhD 19 8 RESONATE-2 (PCYC-1115/1116) Study Design Patients (N=269) Treatment-naïve CLL/SLL with active disease Age 65 years For patients years, comorbidity that may preclude FCR del17p excluded R A N D O M I Z E 1:1 ibrutinib 420 mg once daily until progression chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles CLL progressio n or 1115 study closure PCYC-1116 Extension Study In clb arm, n=55 crossed over to ibrutinib following PD Stratification factors ECOG status (0-1 vs. 2) Rai stage (III-IV vs. II) 3

4 Ibrutinib Prolonged PFS Over Chlorambucil Median PFS not reached (n=136) (n=133) Median PFS 15 mo 88% reduction in the risk of progression or death for patients randomized to ibrutinib Subgroup analysis of PFS revealed benefit was observed across all sub-groups Ibrutinib Significantly Improved PFS in Patients Regardless of IGHV Status (n=40) (n=58) (n=42) (n=60) Ibrutinib led to 83% and 92% reduction in the risk of progression or death in patients with mutated and unmutated IGHV, respectively, compared to chemotherapy Ibrutinib Continues to Demonstrate OS Benefit Over Chlorambucil With Longer Follow-Up and Cross-Over (n=136) (n=133) 4

5 Most Frequent AEs in Ibrutinib Arm Adverse Event, % Grade 1 Ibrutinib Arm (n=135) Grade 2 Grade 3 Grade 4 Additional AEs of clinical interest Major hemorrhage occurred in 7% of ibrutinib-treated patients (1 Grade 2, 7 Grade 3, 1 Grade 4; 5 in first 12 months and 4 between 1-2 years) Atrial fibrillation occurred in 10% of ibrutinib-treated patients (1 Grade 1, 7 Grade 2, 6 Grade 3) AE, adverse event. No PJP occurred Grade 5 Any Grade Diarrhea Fatigue Cough Anemia Nausea Peripheral edema Arthralgia Pyrexia Treatment-Emergent AEs ( Grade 3) Over Time in First- Line Ibrutinib Patients ( 4% Over 29 Months Median Follow-Up) 0-12 months (n=135), % Ibrutinib Arm >12-24 months (n=123), % >24-36 months (n=112), % Neutropenia Pneumonia* Anemia Hypertension Hyponatremia Atrial fibrillation Grade 3 AEs in 4% of patients over the 29 mo follow-up: neutropenia (12%), pneumonia (7%), anemia (7%), hypertension (5%), hyponatremia (4%), and atrial fibrillation (4%) Most Grade 3 AEs in ibrutinib-treated patients decreased over time What do these data tell us? With FCR, early MRD negativity is associated with higher chance of long term remissions/cure IGVH mutated patients who achieve MRD negativity after 3 cycles may not need further therapy, but larger studies are needed Ibrutinib in the front line setting is extremely effective and well tolerated Results of trials comparing chemotherapy to ibrutinib are in high demand 5

6 Therapy for Relapsed CLL 16 Five-Year Experience With Single-Agent Ibrutinib in Patients With Previously Untreated and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Susan O Brien, MD, Richard R. Furman, MD, Steven Coutre, MD, Ian W. Flinn, MD, PhD, Jan Burger, MD, PhD, Kristie Blum, MD, Jeff Sharman, MD, William Wierda MD, PhD, Jeffrey Jones MD, MPH, Weiqiang Zhao, MD, PhD, Nyla A. Heerema, PhD, Amy J. Johnson, PhD, Ying Luan, PhD, Danelle F. James, MD, MAS, Alvina D. Chu, MD, John C. Byrd, MD 17 PCYC-1102/1103 Phase 2 Study Design Phase 2 (PCYC-1102) N=132 Extension Study (PCYC-1103) Patients with CLL/SLL treated with oral, once-daily ibrutinib (420 or 840 mg/day) Treatment Naïve (TN) 65 years n=31 Relapsed/Refracto ry * (R/R) n=101 SD Long-Term Follow-Up * R/R includes patients with high-risk CLL/SLL, defined as progression of disease <24 months after initiation of a chemoimmunotherapy regimen or failure to respond 6

7 Baseline Characteristics Characteristic Median age, years (range) 70 years ECOG performance status Rai stage 0 II III IV Unknown Bulky disease 5 cm 10 cm TN (n=31) 71 (65 84) 74% 74% 26% 0 42% 55% 3% 19% 0 R/R (n=101) 64 (37 82) 34% 43% 53% 4% 38% 57% 5% 54% 15% β 2 microglobulin level >3.0 mg/l 26% 49% Baseline Characteristics (Cont d) Characteristic Cytogenetic abnormalities Del17p Del11q Trisomy 12 Del13q Unmutated IGVH Median lines of prior therapies, n (range) TN (n=31) 6% 3% 26% 55% 48% R/R (n=101) 34% 35% 12% 47% 78% 4 (1 12) 27% 14% 59% Complex karyotype data available for 28% of all treated patients Best Response 100% 80% 60% TN (n=31) R/R (n=101) Total (N=132) 87% 89% 89% 10% 14% 29% CR PR PR-L 40% 20% 55% 76% 71% 0% Median DOR, months (range) Median follow-up, months (range) 3% 3% 3% 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) 21 NR, not reached. 7

8 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% Median OS 5-year OS TN (n=31) NR 92% R/R (n=101) NR 57% NR, not reached. 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% **No del17p, del11q, del13q, or trisomy 12; in hierarchical order for del17p, and then del11q NR, not reached. 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% Survival by Complex Karyotype Progression-Free Survival Overall Survival Median PFS 5-year PFS Complex karyotype (n=41) 33 mo 36% No complex karyotype (n=71) NR 69% Median OS 5-year OS Complex karyotype (n=41) 57 mo 46% No complex karyotype (n=71) NR 84% NR, not reached. 8

9 Survival by Number of Lines of Prior Therapies Progression-Free Survival Overall Survival Median 5-year PFS PFS 0 prior therapies (n=31) NR 92% 1-2 prior therapies* (n=27) 63 mo 60% 3 prior therapies (n=14) 59 mo 41% 4 prior therapies (n=60) 39 mo 38% *Only 2 patients had received 1 prior therapy. NR, not reached. Median 5-year OS OS 0 prior therapies (n=31) NR 92% 1-2 prior therapies* (n=27) 63 mo 60% 3 prior therapies (n=14) NR 85% 4 prior therapies (n=60) 57 mo 47% Onset of Most Grade 3 Adverse Events Decreased Over Time 1 year >1 2 years >2 3 years >3 4 years >4 years *Listed adverse events include those that occurred in 5% of patients in all-treated population; denominator for each term and time period can vary based on those at risk 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; Jennifer Woyach, MD; Farrukh T. Awan, MD; Kami J. Maddocks, MD; Thomas Whitlow, BA; Amy S Ruppert, MAS; and John C. Byrd, MD 27 9

10 Treatment Schema C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 Cycle = 28 days Obinutuzumab 1000 mg IV Ibrutinib 420 mg daily PO Venetoclax (cohort dose) mg daily PO Response assessed (CT + BMBx) After Cycle 8 2 months beyond end Cycle 14 Drugs initiated sequentially to limit risk for tumor lysis syndrome (TLS) All patients discontinue treatment after Cycle 14 Sequential cohorts of 3 underwent dose escalation to target venetoclax dose in Cycle 3 to establish MTD of venetoclax in combination 28 Characteristic Patient Characteristics Age in years, Median (Range) 57 (42-70) Male Gender, no. (%) 11 (92) Median no. Prior Therapies, Median (Range) 1 (1-7) TLS Risk, no. (%) Low Medium High Baseline Peripheral Blood Counts Hemoglobin (g/dl), Median (Range) Platelets(K/uL), Median (Range) Absolute Neutrophil Count (K/uL), Median (Range) Lymphocytes (K/uL), Median (Range) 1 (8) 7 (58) 4 (33) 12.4 ( ) 161 ( ) 5.1 (0-23.5) ( ) Beta-2 Microglobulin (mg/l), Median (Range) 3.3 ( ) Genetic Risk Features, no. (%) Unmutated IgHV Status Zap70 Unmethylated Del(17p) Del(11q) Complex Abnormal Karyotype 11 (92) 7 (58) 1 (8) 8 (67) 5 (42) 29 Treatment-Emergent Gr 3/4 Non-Hematologic AEs Adverse Event Grade 3+ (no., %) Hypertension 3 (25) Hypophosphatemia 3 (25) Fatigue 2 (16.7) Thrombocytopenia 2 (16.7) Headache 1 (8.3) Infusion Related Reaction 1 (8.3) Aspartate Aminotransferase (AST) Increased 1 (8.3) Flu-like Symptoms 1 (8.3) Hypokalemia 1 (8.3) Abdominal Pain 1 (8.3) Blood Bilirubin Increased 1 (8.3) Hypocalcemia 1 (8.3) aptt Prolonged 1 (8.3) Stomach Pain 1 (8.3) No dose-limiting toxicities were recorded at any venetoclaxdose level No cases of laboratory or clinical tumor lysis syndrome (TLS) observed 30 10

11 Treatment-Emergent Hematologic AEs Adverse Event Grade 1/2 No. (%) White Blood Cell Count Decreased Neutrophil Count Decreased Lymphocyte Count Decreased Platelet Count Decreased Grade 3+ No. (%) All Grades No. (%) 7 (58.3) 4 (33.3) 11 (91.7) 5 (41.7) 7 (58.3) 12 (100) 5 (41.7) 5 (41.7) 10 (83.3) 7 (58.3) 2 (16.7) 9 (75) Anemia 2 (16.7) 0 2 (16.7) Neutropenia common, but no Grade 3/4 infections observed 8 cases of Grade 1 infection, no cases of neutropenic fever 5 patients received at least one dose of G-CSF Only 1 patient with baseline neutropenia received >4 doses 31 Cycle 9 Treatment Response Patient ID Cycle 9 Response Peripheral Blood MRD ⱡ (%) Bone Marrow MRD ⱡ (%) Dose Level 1 (venetoclax 100) Dose Level 2 (venetoclax 200) Dose Level 3 (venetoclax 400) PR PR PR PR PR CR PR PR CR PR NR* NR* IWCLL (2008) response; PR = partial response; CR = complete response; NR = not reached ⱡ Measured by four-color flow cytometry, reported as percentage (%) of events * All remain on therapy but had not yet completed 9 cycles of therapy 32 Twice Daily Dosing with the Highly Specific BTK Inhibitor BGB-3111, Achieves Complete and Continuous BTK Occupancy in Lymph Nodes, and is Associated with a Durable Response in Patients with CLL/SLL Constantine S Tam, Stephen Opat, Gavin Cull, Judith Trotman, David Gottlieb, David Simpson, Paula Marlton, Mary Ann Anderson, Matthew Ku, David Ritchie, Sumita Ratnasigam, Bradley Augustson, Mark Kirschbaum, Lai Want, Ling Xue, Eric Hedrick, John F Seymour, Andrew W Roberts 33 11

12 High BTK Occupancy at 160 mg BID 34 Overall Response Rates and Treatment Discontinuation 35 Progression Free Survival 36 12

13 What do these data tell us? Single agent ibrutinib continues to show promise in the relapse setting, although there are likely to be patients that would benefit more from combination therapy or alternate kinase inhibitors The combination of ibrutinib with venetoclax and obinutuzumab appears very promising, and attainment of deeper remissions may facilitate discontinuation Second generation irreversible BTK inhibitors are promising 37 The Post- Ibrutinib Setting 38 The Development and Expansion of Resistant Subclones Precedes Relapse During Ibrutinib Therapy in Patients with CLL Jennifer A. Woyach, Daphne Guinn, Amy S. Ruppert, James S. Blachly, Arletta Lozanski, Nyla Heerema, Weiqiang Zhao, Joshua Coleman, Daniel Jones, Lynne Abruzzo, Amber Gordon, Rose Mantel, Lisa L Smith, Samantha McWhorter, Melanie Davis, Tzyy-Jye Doong, Fan Ny, Margaret Lucas, Weihong Chase, Jeffrey A. Jones, Joseph F. Flynn, Kami Maddocks, Samantha Jaglowski, Leslie A. Andritsos, Farrukh Awan, Kristie Blum, Michael R. Grever, Gerard Lozanski, John C. Byrd, Amy J. Johnson 39 13

14 Factors Related to Discontinuation Median follow-up 3.4 years (range ) 40 Baseline Characteristics Associated with Ibrutinib Discontinuation Variable Transformation CLL Progression Other Event Complex Karyotype (y vs. n) MYC abnormality (y vs. n) HR (95% CI) P HR (95% CI) P HR (95% CI) P 5.00 ( ) 2.15 ( ) Del(17p13.1) on FISH (y vs n) Age, years ( 65 vs <65) Prior therapies >3 (yes vs no) ( ) ( ) 0.49 ( ) ( ) ( ) All models adjusted for monotherapy with ibrutinib versus combination therapy with ibrutinib and ofatumumab, regardless of statistical significance. 41 Association of CLL Progression with BTK and PLCγ2 Mutations Ion Torrent for BTK and PLCγ2 performed on blood or marrow on 46 patients 87% have mutations in BTK or PLCG2 acquired at relapse 31 had BTK C481 as sole mutations 3 had PLCG2 hotspot mutations only 6 have both BTK C481S and PLCG2 hotspot mutations 6 have neither mutation 42 14

15 Resistance Mutations Appear Over Time 43 Resistance Mutations Can Be Detected Prospectively 44 Survival is Poor Following Discontinuation Survival Probability Other Event: Infection (n = 31) Other Event: Not Infection (n = 44) CLL Progression (n = 55) Transformation (n = 28) Months from Ibrutinib Discontinuation 45 15

16 Venetoclax Monotherapy for Patients with CLL who Relapsed After or Were Refractory to Ibrutinib or Idelalisib Jeffrey Jones, Michael Y. Choi, Anthony R. Mato, Richard R. Furman, Matthew S. Davids, Leonard Heffner, Bruce D. Cheson, Nicole Lamanna, Paul M. Barr, Herbert Eradat, Ahmad Halwani, Brenda Chyla, Maria Verdugo, Rod A. Humerickhouse, Jalaja Potluri, William G. Wierda, Steven Coutre 46 Patient Characteristics 47 Objective Response 48 16

17 Progression Free Survival 49 Acalabrutinib Monotherapy in Patients With Ibrutinib Intolerance: Results From the Phase 1/2 ACE-CL-001 Clinical Study Farrukh T. Awan, Anna Schuh, Jennifer R. Brown, Richard R. Furman, John M. Pagel, Peter Hillmen, Deborah M. Stephens, Ahmed Hamdy, Raquel Izumi, Priti Patel, Min Hui Wang, John C. Byrd 50 Acalabrutinib Kinase Profile Kinase Selectivity Profiling at 1 mol/l 1 Kinase Inhibition IC 50 (nmol/l) 1 Acalabrutinib Ibrutinib Kinase Acalabrutinib Ibrutinib BTK Larger red circles represent stronger inhibition TEC BMX TXK ERBB2 ~ EGFR > ITK > JAK3 > BLK >

18 Reasons for Ibrutinib Discontinuation 52 Patient Disposition Median time on treatment: 12.2 months (range, months) 53 Recurrence of Ibrutinib-Related AEs A total of 12 of 33 (36%) patients experienced a recurrent AE. 14 of 16 events either decreased or were unchanged in severity with acalabrutinib treatment No patients discontinued acalabrutinib because of a prior ibrutinib-related AE

19 What do these data tell us? Patients with high genetic risk CLL are most at risk for progression on ibrutinib Outcomes following ibrutinib discontinuation are poor, especially for patients who transform Venetoclax is active in patients after kinase inhibitors, but trials of other agents and combinations are needed Patients who discontinue ibrutinib due to toxicity do fairly well, and may be able to be treated with second generation BTK inhibitors 55 Richter s Transformation 56 Nivolumab Combined with Ibrutinib for CLL and Richter Transformation A Phase II Trial Nitin Jain, Sreyashi Basu, Philip A Thompson, Maro Ohanian, Alessandra Ferrajoli, Naveen Pemmaraju, Jorge Cortes, Zeev Estrov, Jan A Burger, Sattva S. Neelapu, Wanda Lopez, Beenu Thakral, Carlos E. Bueso-Ramos, Jorge Blando, Susan O'Brien, Hagop Kantarjian, James Allison, Michael Keating, Padmanee Sharma, William G. Wierda 57 19

20 Efficacy in Richter s Transformation yr old TP53 mutated CLL Unmutated IGHV Complex cytogenetics 4 prior therapies (FCR, BR, obinutuzumab/ HDMP, idelalisib) EBER Neg Nivo + Ib for R/R CLL and RT Responses in RT #1 Nivolumab start C1D1 Ibrutinib start C1D15 Efficacy in CLL 60 20

21 Conclusions This remains a very exciting time in CLL research, and new therapies have the potential to significantly improve patients lives CIT is still an excellent option for some patients, and there may be opportunity to limit exposure for some Ibrutinib and other BTK inhibitors are very effective single agents for both TN and R/R CLL Venetoclax is effective in patients who relapse on ibrutinib Checkpoint inhibitors are a promising therapy for Richter s Transformation 61 21