Chronic Lymphocytic Leukemia: State of the Art

Transcription

1 14th Annual INDY Hematology Review March 2017 Chronic Lymphocytic Leukemia: State of the Art Adrian Wiestner, MD/PhD Bethesda, MD

2 Disclosures Grant/research support: Pharmacyclics Acerta Pharma Off-label/investigative use(s): Ibrutinib with chemotherapy or antibody therapy Idelalisib in combination with chemotherapy

3 CLL8 study (FCR vs FC): improved outcome with chemoimmunotherapy Progression free survival Overall survival FC & Rituximab: 52 months Cyclophosphamide plus Fludarabine (FC): 33 months del 17p Hallek et al. Lancet, 2010

4 P e r c e n t p r o g r e s s io n -fr e e Long term disease free survival in patients with IGHV mutated CLL treated with FCR MD Anderson experience CLL8 study: FC vs FCR N P ro g -fre e IG H V m u ta te d IG H V u n m u ta te d IGHV mutated, FCR (n=113) 5 0 mutated, FC 2 5 p < n= T im e (Y e a rs ) Thompson et al, Blood 2015 Courtesy of Ph. Thompson Fischer et al, Blood 2015

5 MRD-negative strongly associated with PFS but modified by IGHV mutation status Thompson et al, abstract #232

6 Patients with mutated IGHV have very favorable outcomes, even with only 3 courses of FCR Thompson et al, abstract #232

7 CLL10 STUDY: FCR VS BR IN FRONT-LINE Progression-free survival, Median follow-up 37 months All patients Patients >65 years: FCR (31%), BR (39%) Median PFS FCR 55.2 months BR 41.7 months P < Median PFS FCR not reached BR 48.5 months P = 0.17 BR has inferior PFS (HR = 1.6) than FCR, less AEs, no difference in OS

8 Progression free survival Progression free survival Chemoimmunotherapy for unfit patients (CLL11 study) Addition of obinutuzumab to chlorambucil Obinutuzumab & Clb vs Rituximab & Clb HR: 0.18 P < HR: 0.40 P < Months on study Months on study Goede et al, NEJM 2014; Leukemia 2015.

9 Kinase inhibitors to target B-cell receptor signaling Wiestner, Haematologica 2015

10 Progression free survival (%) Randomized phase 3 studies in rel/ref CLL Ibrutinib vs ofatumumab Rituximab with idelalisib vs Rituximab with placebo ORR: 43% vs 4.1% ORR: 81% vs 13% ibrutinib Idelalisib + ritux Median 8.1 months ofatumumab Median 5.5 months Placebo + ritux Months Byrd et al, NEJM 2014 Months Furman et al, NEJM 2014

11 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. ASH 2016, year Update; O Brien et al.

12 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. ASH 2016, year Update; O Brien et al.

13 Survival by Number of Lines of Prior Therapies Progression-Free Survival Overall Survival Median PFS 5-year 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 OS 5-year 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% ASH 2016, year Update; O Brien et al.

14 Cumulative Frequency of Grade 3 Adverse Events Over 5-Year Follow-Up Non-hematologic 5% Hematologic Infectious R/R TN R/R TN R/R TN Grade 3 Grade 4 Grade 5 ASH 2016, year Update; O Brien et al.

15 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 progression 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) Efficacy (PFS, OS, ORR) determined by investigator-assessment. *Patients could enroll in separate extension study PCYC-1116 after independent review committee-confirmed PD or at study PCYC-1115 closure for continuing treatment and follow-up. ASH 2016, Updated Efficacy/Safety RESONATE-2; Barr et al.

16 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 ASH 2016, Updated Efficacy/Safety RESONATE-2; Barr et al.

17 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 ASH 2016, Updated Efficacy/Safety RESONATE-2; Barr et al.

18 Ibrutinib Continues to Demonstrate OS Benefit Over Chlorambucil With Longer Follow-Up and Cross-Over (n=136) (n=133) ASH 2016, Updated Efficacy/Safety RESONATE-2; Barr et al.

19 Most Patients Remain on Ibrutinib Treatment Median duration of ibrutinib treatment, mo (range) Treatment duration, n (%) 12 months >12-24 months >24-36 months First-line ibrutinib (n=135) 29 (1-36) 14 (10) 9 (7) 112 (83) Continuing ibrutinib on study, n (%) 107 (79) Discontinued ibrutinib, n (%) Disease Progression AEs Death Withdrawal of consent Investigator decision 28 (21) 4 (3) 16 (12) 6 (4) 2 (1) 0 79% of patients continue on ibrutinib treatment on study with 83% of patients receiving at least 2 years of treatment ASH 2016, Updated Efficacy/Safety RESONATE-2; Barr et al.

20 Most Frequent AEs in Ibrutinib Arm Adverse Event, % 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 1 Ibrutinib Arm (n=135) Grade 2 Grade 3 Grade 4 Grade 5 Any Grade Diarrhea Fatigue Cough Anemia Nausea Peripheral edema Arthralgia Pyrexia ASH 2016, Updated Efficacy/Safety RESONATE-2; Barr et al.

21 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 ASH 2016, Updated Efficacy/Safety RESONATE-2; Barr et al.

22 Acalabrutinib (ACP-196) in relapsed/refractory CLL/SLL Response over time Progression free survival Median follow-up 14 months Byrd et al, NEJM 2015

23 Acalabrutinib Monotherapy in Patients With Ibrutinib Intolerance: Results From the Phase 1/2 ACE-CL-001 Clinical Study Farrukh T. Awan, 1 Anna Schuh, 2 Jennifer R. Brown, 3 Richard R. Furman, 4 John M. Pagel, 5 Peter Hillmen, 6 Deborah M. Stephens, 7 Ahmed Hamdy, 8 Raquel Izumi, 8 Priti Patel, 8 Min Hui Wang, 8 John C. Byrd 1 1 The Ohio State University Comprehensive Cancer Center, Columbus, OH; 2 University of Oxford, Oxford, UK; 3 Dana-Farber Cancer Institute, Boston, MA; 4 Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY; 5 Swedish Medical Center, Seattle, WA; 6 St. James s University Hospital, Leeds, UK; 7 University of Utah Huntsman Cancer Institute, Salt Lake City, UT; 8 Acerta Pharma, Redwood City, CA 23

24 Awan F, et al. ASH 2016 Adverse Events Experienced on Ibrutinib ( 2 Patients) (Investigator Assessed; N=33) Adverse Event, n (%) Grade 1 Grade 2 Grade 3 Unknown Total Rash 3 (9) 1 (3) 2 (6) 0 7 (21) Arthralgia 1 (3) 2 (9) 2 (6) 0 6 (18) Diarrhea 1 (3) 1 (3) 2 (6) 1 (3) 5 (15) Fatigue 2 (6) 1 (3) 1 (3) 0 4 (12) Hemorrhage 2 (6) 0 1 (3) 1 (3) 4 (12) Myalgia 1 (3) 1 (3) 1 (3) 0 3 (9) Atrial fibrillation 0 2 (6) (6) Erythema nodosum 0 2 (6) (6) Hematoma 1 (3) 1 (3) (6) Multiple occurrences of the same AE for a given patient were counted once for each Preferred Term. Patients may have experienced 1 AE. Resolution of ibrutinib-related AEs was not required prior to study entry. 24

25 Awan P, et al. ASH 2016 Conclusions Acalabrutinib was well tolerated in ibrutinib-intolerant patients. A total of 12 of 33 (36%) patients experienced AE recurrence, most of which were decreased or the same severity. No patients discontinued because of a recurrent AE. Acalabrutinib has promising activity in ibrutinib-intolerant patients. ORR: 79% 81% of responding patients have a duration of response (PRL or better) 12 months. Median PFS has not been reached. Acalabrutinib efficacy in ibrutinib-intolerant patients is being evaluated in an ongoing phase 2 trial (NCT ). 25

26 Cumulative Incidence of Discontinuation 26

27 Mutations in BTK and PLCγ2 confer ibrutinib resistance 20 of 246 CLL patients (8%) had secondary resistance (>6months on therapy); eight with transformation. Acquired mutations in six patients: C481S mutation in five, activating mutations in PLCg2 in two Woyach, NEJM 2014; Furman, NEJM 2014; Liu, Blood 2015 Wiestner, Haematologica 2015

28 Resistance Mutations Appear Over Time

29 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 29

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35 Venetoclax (ABT-199) Venetoclax is an orally bioavailable, selective BCL2 inhibitor, directly inducing apoptosis in CLL cells independent of p53 1 Increased BCL-2 Expression Venetoclax Binds to and Apoptosis is Initiated Allows Cancer Cell to Survive Inhibits Overexpressed Apoptosome BCL-2 Venetoclax Pro-apoptotic Proteins (BAX, BAK) Anti-apoptotic Proteins (BCL-2) 2 BH3-only BAX BAK BCL-2 BCL-2 3 APAF-1 Cytochrome c Active Caspase Procaspase Mitochondria Mitochondria Mitochondria First-in-human study of venetoclax showed a 79% ORR in relapsed/refractory CLL (Roberts AW et al., NEJM 2015) 35

36 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 1 The Ohio State University, Columbus, OH; 2 UCSD Moores Cancer Center, San Diego, CA; 3 Center for CLL, University of Pennsylvania, Philadelphia, PA; 4 Weill Cornell Medicine, New York, NY; 5 Dana-Farber Cancer Institute, Boston, MA; 6 Emory University School of Medicine, Atlanta, GA; 7 Georgetown University Hospital, Washington, DC; 8 Columbia University Medical Center, New York, NY; 9 Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY; 10 University of California Los Angeles, CA; 11 University of Utah Healthcare, Salt Lake City, Utah; 12 AbbVie Inc., North Chicago, IL; 13 University of Texas MD Anderson Cancer Center, Houston, TX; 14 Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA American Society of Hematology San Diego, California 5 December 2016

37 A r m B A rm A Current Status Median time on study (range): Arm A, 13 months (0.1 18); Arm B, 9 months (1.3 16) # P D # # # # * # P D P D -R T # # # # # P D P D P D P D P D P D P D P D -R T P D # # P D A rm A (R /R ib ru tin ib ) A rm B (R /R id e la lis ib ) D is c o n tin u e d # P D P D C R i a s b e s t re s p o n s e * M R D n e g a tiv e in b lo o d # T im e o n v e n e to c la x, m o n th s PD, progressive disease. PD-RT, progressive disease due to Richter's transformation. Early discontinuations were due to AEs (n=3) and withdrawn consent (n=1). 37 Data as of 10June2016

38 P a tie n ts w ith R e s p o n s e (% ) P r o g re s s io n -fre e s u rv iv a l (% ) 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%) D u ra tio n o f R e s p o n s e P ro g re s s io n -F re e S u rv iv a l A rm A (R /R ib ru tin ib ) A rm B (R /R id e la lis ib ) 2 5 A rm A (R /R ib ru tin ib ) A rm B (R /R id e la lis ib ) 0 A ll p a tie n ts A ll p a tie n ts M o n th s s in c e firs t d o s e M o n th s s in c e firs t d o s e N o. a t r is k Data as of 10June2016

39 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 No clinical TLS was observed; 1 patient with high tumor burden met Howard criteria for laboratory TLS 6 (9) 5 (8) 2 (3) 2 (3) 2 (3) 39 Data as of 10June2016

40 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, MD 1 1 Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 2 The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH American Society of Hematology San Diego, California 5 December 2016 The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

41 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 41

42 42 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 venetoclax dose level No cases of laboratory or clinical tumor lysis syndrome (TLS) observed

43 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 43

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