Winship Cancer Institute of Emory University Updates in the Management of CLL Susan O’Brien, MD Professor of Medicine Department of Leukemia University of Texas M. D. Anderson Cancer Center Disclosures • Consulting Fees from: – Amgen, Celgene, Emergent, Genentech, Gilead Sciences, Glaxo Smith Kline, Infinity, Pharmacyclics, Spectrum • Advisory Board: CLL Global Research Foundation • Research Support from: ─ Acerta, Emergent, Genentech, Gilead Sciences, Infinity, MorphoSys, Pharmacyclics, Spectrum, TG Therapeutics 1
Targeting of BCR Signaling in CLL BCR-associated kinases • are targets of new drugs in preclinical and clinical development Syk (spleen tyrosine • kinase) inhibitors: R406, Portola’s Syk inhibitors 1 Btk (Bruton’s tyrosine • kinase) inhibitors: ibrutinib, CC-292, ONO- 4059, ACP196 PI3 kinases: Isoform- • Selective Inhibitor of PI 3-Kinases 2 , idelalisib, IPI-145, TGR-1202 1 Quiroga MP, et al. Blood 114(5):1029-37, 07/2009 2 Niedermeier M, et al. Blood 113(22):5549-57, 5/2009 Novel BCR-Directed Agents for CLL ASH 2013 Therapy - Abstracts Agent ORR Poster Abstract #’s BTK inhibitors Ibrutinib 71 – 88% 1631; 4163; 4166; 4182 CC-292 31-67% (PR) 1630; 4169 ONO-4059 70% (PR) Oral ACP-196 — — PI3K Υ / δ inhibitors Idelalisib 72-100% 1632; 2878; 4176; 4180 GS-9820 — 2881 IPI-145 52% 1633; 4167 AMG 319 — Oral TGR-1202 — 4373 SAR245408 (XL147) — 4170 Syk inhibitors GS-9973 — 1634 Fostamatinib 55% — PRT-2070 — — ASH Annual Meeting. 2013. New Orleans, LA. 2
Ibrutinib in Refractory CLL With 11q Deletion 4 weeks Before Pattern of Response: Blood Lymphocytes vs. Lymph Nodes 550 25 ALC SPD 450 0 350 ‐ 25 250 ‐ 50 150 ‐ 75 50 ‐ 50 ‐ 100 0 1 2 3 4 5 6 7 8 9 1 0 1 1 0 1 2 3 4 5 6 7 8 9 0 1 1 1 Month Month SPD = sum of products of lymph node dimension 3
Ibrutinib Inhibits CLL Cell Migration Towards CXCL12 and CXCL13 *(0.055) *(0.072) *(0.048) *(0.059) Hollenriegel et al. ASH 2012 Ibrutinib Treatment Reduced Plasma CCL3 and CCL4 Levels in Patients (N=28) * * * * * * * * * * * * Hollenriegel et al. ASH 2012 4
Best Response (Investigator-Assessed) 100% 90% 89% 87% 6% 8% CR 80% 13% 1% nPR 3% PR PR+L 60% SD PD 80% 77% 40% 65% 20% 2% 2% 0% 6% 6% 4% 4% 5% 5% 0% TN (n = 31) R/R (n = 101) Total (N = 132) 30 Month DOR, % (95% CI) 100 (100 to 100) 79.1 (64.2 to 88.4) 85.3 (74.4 to 91.8) Median DOR, NR (0 to 35.0+) NR (0 to 35.2+) NR (0 to 35.2+) months (range) 5/6 patients who received prior idelalisib responded to ibrutinib (4PR, 1 PR+L) 2/5 responders continue treatment with one additional patient moving on to SCT American Society of Clinical Oncology 2014, PCYC 1102/1103, O’Brien et al. Platelet Counts and Hemoglobin Levels * 140 130 120 Mean Hemoglobin +/ ‐ SEM (g/L) Mean Platelets +/ ‐ SEM (10 9 /L) 130 110 100 120 90 110 80 70 100 Hemoglobin 60 Platelets 90 50 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Months Patients with Results Hemoglobin 53 52 48 46 44 40 42 41 40 38 42 40 39 38 36 35 27 31 21 24 15 13 Platelets 61 61 59 56 55 52 52 49 47 45 50 45 44 47 42 42 35 37 28 27 23 14 American Society of Clinical Oncology 2014, PCYC 1102/1103, O’Brien et al. *All treated patients with baseline anemia or thrombocytopenia 5
Progression-Free Survival 100 90 Progression ‐ Free Survival (%) 80 70 60 50 40 TN R/R 30 30-month PFS 96.3% 68.4% TN 20 (95% CI) (76.5–99.5) (56.1–77.9) R/R 10 Median PFS Not reached Not reached + Censored 0 0 6 12 18 24 30 36 42 Months American Society of Clinical Oncology 2014, PCYC 1102/1108, O’Brien et al. American Society of Clinical Oncology 2014, PCYC 1102/1103, O’Brien et al. 11 Progression ‐ Free Survival by Cytogenetics (FISH) in Relapsed/Refractory Population 1.0 Progression ‐ Free Survival (Proportion) 0.8 0.6 No del17p/ Del17p Del11q 0.4 11q 30 ‐ month 45.9% 74.2% 89.0% PFS del17p 0.2 del11q (95% CI) (25.0–64.6) (53.3–86.8) (69.0–96.4) Median No del17p or del11q 28.1 months Not reached Not reached PFS + Censored 0 0 6 12 18 24 30 36 42 Months From Initiation of Study Treatment American Society of Clinical Oncology 2014, PCYC 1102/1103, O’Brien et al. 12 6
Overall Survival 100 90 Overall Survival (%) 80 70 60 50 40 30 TN R/R 30-month OS 96.6% 79.9% 20 TN (95% CI) (77.9–99.5) (69.0–87.3) R/R 10 + Censored Median OS Not reached Not reached 0 0 6 12 18 24 30 36 42 Months American Society of Clinical Oncology 2014, PCYC 1102/1108, O’Brien et al. American Society of Clinical Oncology 2014, PCYC 1102/1103, O’Brien et al. 13 Overall Survival by Cytogenetics (FISH) in Relapsed/Refractory Population 1.0 0.8 Overall Survival (Proportion) 0.6 Del17p Del11q No del17p/11q 0.4 30 ‐ month 65.9% 84.9% 93.9% OS del17p (95% CI) (45.5–80.2) (64.5–94.0) (77.8–98.4) del11q 0.2 No del17p or del11q Median OS Not reached Not reached Not reached + Censored 0 0 6 12 18 24 30 36 42 Months From Initiation of Study Treatment American Society of Clinical Oncology 2014, PCYC 1102/1103, O’Brien et al. 7
Ibrutinib: Common AEs (All Grades, Regardless of Causality) TN R/R + HR (n = 31) (n = 85) Diarrhea Nausea Fatigue Rash Arthralgia Dyspepsia Rash Arthralgia Muscle spasms Hypertension Hypertension Dizziness URI Nausea Urinary tract… 0% 20% 40% 60% 80% 0% 20% 40% 60% 80% Grade 1 Grade 2 Grade 3 Grade 4 IWCLL 2013, PCYC 1102, Furman et al. RESONATE™ Phase 3 Study Design Oral ibrutinib 420 mg once R daily until PD or A unacceptable toxicity N Patients with n=195 D previously 1:1 O treated M CLL/SLL IV ofatumumab initial dose Cross over to ibrutinib 420 I of 300 mg followed by 2000 mg once daily after IRC Z mg x 11 doses over 24 weeks confirmed PD (n=57) E n=196 • Primary Endpoint: PFS • Stratification according to: – Disease refractory to purine analog chemoimmunotherapy (no response or <12 months) – Presence or absence of 17p13.1 (17p del) • At time of interim analysis, median time on study was 9.4 months Protocol amended for cross over with support of Data Monitoring Committee and discussion with health authorities. PD, progressive disease. 8
Progression-Free Survival 100 Ofatumumab Ibrutinib Progression ‐ Free Survival (%) 90 Median 8.08 NR 80 time (mo) Hazard 0.215 70 ratio 60 (95% CI) (0.146 ‐ 0.317) 50 Log ‐ rank < 0.0001 40 P value 30 NR, not reached 20 Ibrutinib 10 Ofatumumab 0 0 3 6 9 12 15 Months No. at risk Ibrutinib: 195 183 116 38 7 Ofatumumab: 196 161 83 15 1 0 • This represents a 78% reduction in the risk of PD or death with ibrutinib compared with ofatumumab • Richter’s transformation was confirmed in 2 patients on each arm. • Another patient on the ibrutinib arm had transformation to prolymphocytic leukemia Overall Survival Ibrutinib (n=195, 16 events) Ofatumumab (n=196, 33 events) First patient cross over Ofatumumab Ibrutinib Median time (mo) NR NR Hazard ratio 0.434 (95% CI) (0.238 ‐ 0.789) Log ‐ rank P value < 0.0049 NR, not reached This represents a 57% reduction in the risk of death for the ibrutinib arm At the time of this analysis, 57 patients initially randomized to ofatumumab were crossed over to receive ibrutinib following IRC- confirmed PD 9
Safety: Atrial Fibrillation and Bleeding- related Adverse Events Atrial fibrillation any grade: ibrutinib n=10, ofatumumab n=1 • – Discontinuation of ibrutinib in only 1 patient Patients were ≥ 60 years old (median age 73) Most had predisposing risk factors (a prior history of atrial fibrillation or in the setting of a pulmonary infection) Bleeding-related AEs of any grade: • most commonly petechiae and ecchymoses ibrutinib 44%, ofatumumab 12% – No difference in severe/major bleeding events: ibrutinib n=2, ofatumumab n=3, 1 SDH with ibrutinib – One patient discontinued ibrutinib due to a bleeding AE – Concomitant anti-platelets or anticoagulants 50% ibrutinib and 39% ofatumumab 19 Ibrutinib and Rituximab (iR) in High-risk CLL Rituximab Month 1 Month 2 - 6 Month 7-12 (375 mg/m2) Day 1 8 15 21 1 1 1 1 1 1 2 3 4 5 Cycle Ibrutinib 6 420 mg/d PO once daily Patients with benefit after 12 cycles continue on ibrutinib Burger et al. ASH 2013 10
Transient lymphocytosis on iR n=40 Absolute lymphocyte n=40 n=40 count (per µL) n=40 n=40 n=38 n=39 n=28 n=23 n=32 n=37 n=38 n=23 n=17 n=25 n=10 n=11 n=17 Week 2 Week 3 Week 1 Start of 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 1 st Month Months Best Response* (n=40) N % CR # 4 10 PR 34 85 ORR 37 95 NR 2 5 *At 12 months or best response before study discontinuation # MRD-negative: 1/4, MRD level: 0.1, 0.2, 0.1% 11
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