Updates in the Management of CLL Susan OBrien, MD Professor of - - PDF document

1 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

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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 inhibitors1

• Btk (Bruton’s tyrosine

kinase) inhibitors: ibrutinib, CC-292, ONO- 4059, ACP196

• PI3 kinases: Isoform-

Selective Inhibitor of PI 3-Kinases2, 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

Agent ORR Poster Abstract #’s

BTK inhibitors Ibrutinib CC-292 ONO-4059 ACP-196 71 – 88% 31-67% (PR) 70% (PR) — 1631; 4163; 4166; 4182 1630; 4169 Oral — PI3KΥ/δ inhibitors Idelalisib GS-9820 IPI-145 AMG 319 TGR-1202 SAR245408 (XL147) 72-100% — 52% — — — 1632; 2878; 4176; 4180 2881 1633; 4167 Oral 4373 4170 Syk inhibitors GS-9973 Fostamatinib PRT-2070 — 55% — 1634 — —

Novel BCR-Directed Agents for CLL ASH 2013 Therapy - Abstracts

ASH Annual Meeting. 2013. New Orleans, LA.

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Ibrutinib in Refractory CLL With 11q Deletion

Before 4 weeks Pattern of Response: Blood Lymphocytes vs. Lymph Nodes

SPD

1 2 3 4 5 6 7 8 9 1 1 1 550 450 350 250 150 50 ‐50

ALC Month Month

‐100 ‐75 ‐50 ‐25 25 1 2 3 4 5 6 7 8 9 1 1 1

SPD = sum of products of lymph node dimension

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Ibrutinib Inhibits CLL Cell Migration Towards CXCL12 and CXCL13

*(0.059) *(0.055) *(0.048) *(0.072)

Hollenriegel et al. ASH 2012

Ibrutinib Treatment Reduced Plasma CCL3 and CCL4 Levels in Patients (N=28)

* * * * * * * * * * * *

Hollenriegel et al. ASH 2012

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American Society of Clinical Oncology 2014, PCYC 1102/1103, O’Brien et al.

0% 2% 2% 6% 4% 5% 6% 4% 5% 65% 80% 77% 3% 1% 13% 6% 8% 0% 20% 40% 60% 80% 100%

Best Response (Investigator-Assessed)

87% 90% 89%

30 Month DOR, % (95% CI) TN (n = 31) 100 (100 to 100) R/R (n = 101) 79.1 (64.2 to 88.4) Total (N = 132) 85.3 (74.4 to 91.8) Median DOR, months (range) NR (0 to 35.0+) NR (0 to 35.2+) NR (0 to 35.2+)

nPR CR PR PR+L SD PD

• 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.

Mean Hemoglobin +/‐ SEM (g/L) Months 90 50 100 110 120 130 140 2 Hemoglobin Platelets

Platelet Counts and Hemoglobin Levels*

4 6 8 10 12 14 16 18 20 22 24 26 28 30 60 70 80 90 100 110 120 130 Mean Platelets +/‐ SEM (109/L)

Hemoglobin Platelets 53 61 52 61 48 59 46 56 44 55 40 52 42 52 41 49 40 47 38 45 42 50 40 45 39 44 38 47 36 42 35 42 27 35 31 37 21 28 24 27 15 23 13 14 Patients with Results *All treated patients with baseline anemia or thrombocytopenia

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American Society of Clinical Oncology 2014, PCYC 1102/1103, O’Brien et al.

10 20 30 40 50 60 70 80 90 100

Progression‐Free Survival (%)

6 12 18 24 30 36 42 Months TN R/R + Censored

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Progression-Free Survival

TN R/R 30-month PFS 96.3% 68.4% (95% CI) (76.5–99.5) (56.1–77.9) Median PFS Not reached Not reached

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.

0.2 0.4 0.6 0.8 1.0 Progression‐Free Survival (Proportion) 6 12 18 24 30 36 42 Months From Initiation of Study Treatment

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Progression‐Free Survival by Cytogenetics (FISH) in Relapsed/Refractory Population

Del17p Del11q No del17p/ 11q 30‐month PFS 45.9% 74.2% 89.0% (95% CI) (25.0–64.6) (53.3–86.8) (69.0–96.4) Median PFS 28.1 months Not reached Not reached del17p del11q No del17p or del11q

+ Censored

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American Society of Clinical Oncology 2014, PCYC 1102/1103, O’Brien et al.

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Overall Survival

TN R/R 30-month OS 96.6% 79.9% (95% CI) (77.9–99.5) (69.0–87.3) Median OS Not reached Not reached 10 20 30 40 50 60 70 80 90 100

Overall Survival (%)

6 12 18 24 30 36 42 Months TN R/R + Censored

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.

Overall Survival by Cytogenetics (FISH) in Relapsed/Refractory Population

Del17p Del11q No del17p/11q 30‐month OS 65.9% 84.9% 93.9% (95% CI) (45.5–80.2) (64.5–94.0) (77.8–98.4) Median OS Not reached Not reached Not reached 0.2 0.4 0.6 0.8 1.0 Overall Survival (Proportion) 6 12 18 24 30 36 42 Months From Initiation of Study Treatment + Censored del17p del11q No del17p or del11q

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Ibrutinib: Common AEs (All Grades, Regardless of Causality)

IWCLL 2013, PCYC 1102, Furman et al.

TN (n = 31) R/R + HR (n = 85) 0% 20% 40% 60% 80% Nausea Dizziness Hypertension Muscle spasms Rash Arthralgia Fatigue Diarrhea 0% 20% 40% 60% 80% Urinary tract… URI Hypertension Arthralgia Dyspepsia Rash Nausea

Grade 3 Grade 1 Grade 2 Grade 4

• 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

RESONATE™ Phase 3 Study Design

R A N D O M I Z E

Oral ibrutinib 420 mg once daily until PD or unacceptable toxicity n=195 IV ofatumumab initial dose

• f 300 mg followed by 2000

mg x 11 doses over 24 weeks n=196

1:1 Patients with previously treated CLL/SLL

Protocol amended for cross over with support of Data Monitoring Committee and discussion with health authorities. PD, progressive disease.

Cross over to ibrutinib 420 mg once daily after IRC confirmed PD (n=57)

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Progression-Free Survival

3 6 9 12 195 183 116 38 7 196 161 83 15 1 15 10 20 30 40 50 60 70 80 90 100

Progression‐Free Survival (%)

• No. at risk

Ibrutinib: Ofatumumab:

Months

Ibrutinib Ofatumumab

Ofatumumab Ibrutinib Median time (mo) 8.08 NR Hazard ratio 0.215 (95% CI) (0.146‐0.317) Log‐rank P value < 0.0001

• This represents a 78% reduction in the risk of PD or death with ibrutinib compared with
• fatumumab
• Richter’s transformation was confirmed in 2 patients on each arm.
• Another patient on the ibrutinib arm had transformation to prolymphocytic leukemia

NR, not reached

Overall Survival

Ofatumumab Ibrutinib Median time (mo) NR NR Hazard ratio 0.434 (95% CI) (0.238‐0.789) Log‐rank P value < 0.0049

Ibrutinib (n=195, 16 events) Ofatumumab (n=196, 33 events)

• 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
• fatumumab were crossed over to receive ibrutinib following IRC-

confirmed PD

NR, not reached

First patient cross over

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• 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

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Safety: Atrial Fibrillation and Bleeding- related Adverse Events

Month 2 - 6 Month 1

Day 1 8 15 21 1 1 1 1 1

Ibrutinib

420 mg/d PO

• nce daily

Ibrutinib and Rituximab (iR) in High-risk CLL

Rituximab

(375 mg/m2) Cycle

1 2 3 4 5 6 Month 7-12

Patients with benefit after 12 cycles continue on ibrutinib

Burger et al. ASH 2013

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Transient lymphocytosis on iR

Absolute lymphocyte count (per µL)

Start of 1st Month

Week 2 Week 3

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 n=40 n=40 n=40 n=40 n=40 n=37 n=39 n=38 n=38 n=28 n=32 n=11 n=17 n=23 n=23 n=17 n=25 n=10

Months

Week 1

N % CR# 4 10 PR 34 85 ORR 37 95 NR 2 5

Best Response* (n=40)

*At 12 months or best response before study discontinuation

# MRD-negative: 1/4, MRD level: 0.1, 0.2, 0.1%

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Progression-free Survival (PFS)

• f iR in Previously Treated CLL

0.00 0.25 0.50 0.75 1.00 Proportion without progression/death 2 4 6 8 10 12 14 16 18 20 22 24 Months 0.00 0.25 0.50 0.75 1.00 Proportion Surviving 2 4 6 8 10 12 14 16 18 20 22 24 Months No: del 17p del 17p

Median PFS at 18 months: 78%

All patients Del 17p versus others

Median PFS at 18 months: Del17p: 72% Others: 84%

Median follow-up: 17 months

Idelalisib is an Orally Bioavailable Small Molecule that Inhibits PI3K Delta Potently and Selectively

Class I PI3K Isoform Cell- Based Activity PDGF- induced pAKT LPA- induced pAKT fMLP- induced CD63+ FcR1- induced CD63+ EC50 (nM) >20,000 1,900 3,000 8 Alpha Beta Gamma Delta

• Selectivity relative to Class I PI3K isoforms involved in insulin signaling and other

physiological functions

• No off-target activity against Class II or III PI3K, mTOR, or DNA-PK
• No off-target activity seen in screen of >350 protein kinases (Ambit KINOMEscan™)

Lannutti, Blood, 2011

Idelalisib

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TSt‐4: Idelalisib TSt‐4: Control

Idelalisib Antagonizes BCR-Triggered CLL Cell Migration (Pseudoemperipolesis) Beneath Bone Marrow Stroma Cells

Marked Reductions in Peripheral Lymphadenopathy Were Observed

Pretreatment With IdelalisibTreatment

38-year-old patient with refractory CLL and 5 prior therapies

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Idelalisib: Idelalisib Improvement

• f Baseline Cytopenias

Brown et al. ASCO 2013

Idelalisib: Nodal and Overall Response Rate

20 40 60 80 100

Response Rate 95% CI Overall Response Lymph Node Response 39% n=21 33% n=18

81% n=44 72% n=39

Decrease by 50% of nodal SPD PR with lymphocytosis (Cheson 2012) PR by IWCLL criteria (Hallek 2008)

ALC (N=54) SPD (N=51)

ALC and Tumor Burden Over Time

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Idelalisib: Progression-free Survival by Dose

Brown et al. Blood. 2014; e-publication, March 10, 2014. Time from Start of Idelalisib, Months % Progression‐Free

6 12 18 24 30 36 42 48 25 50 75 100

≥150 mg BID (N=28): median PFS 31.9 months <150 mg BID (N=26): median PFS 6.6 months

Idelalisib: Adverse Events (≥ 15%) and Selected Lab Abnormalities (N = 54)

AE, n (%) Any Grade, (%) Grade  3, (%) Fatigue 17 (32) 1 (2) Diarrhea 16 (30) 3 (6) Pyrexia 16 (30) 2 (4) Cough 13 (24) 2 (4) Back pain 12 (22) Rash 12 (22) URI 12 (22) Pneumonia 11 (20) 10 (19) Night sweats 10 (19) Chills 9 (17) Laboratory abnormality, n (%) AST, increased* 13 (24) 1 (2) ALT, increased* 10 (19) 1 (2) *15 subjects total with transaminase elevations

Brown et al ASCO 2013

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Phase 2 Single Arm, Open Label Study of Idelalisib + Rituximab in Frontline CLL

Study Schema

Primary Study: 101-08 Extension Study: 101-99

Subject accrual Oct 2010 through Apr 2012

Eligibility

• Age ≥ 65 years
• Treatment naive CLL requiring therapy (IWCLL

2008)

• No exclusions for cytopenias

Disease assessment

• Investigator determined
• Weeks 0, 8, 16, 24, 36, 48 and per SOC thereafter

Endpoints

• Primary: ORR
• Secondary: DOR, PFS, Safety

Rituximab (375 mg/m2) weekly x 8

Therapy continues as long as patient receives benefit Idelalisib (150 mg BID) x 48 wks

O’Brien et al ASCO 2013

Idelalisib + Rituximab: Response

All Patients Del(17p) and/or TP53 mutation N = 64 (%) N = 9 (%) Complete Response 12 (19) 3 (33) Partial Response 50 (78) 6 (67) Stable Disease Progressive Disease Not Evaluable 2 (3) Overall Response 62 (97) 9 (100)

• Median Time to Response 1.9 months
• 24/26 patients with B symptoms resolved by week 16

No on-study progression

O’Brien et al ASCO 2013

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Deaths (n = 5)

• Pneumonia/sepsis (1)
• Pneumonia/metastatic melanoma (1)
• Pneumonitis (2)
• Myocardial infarction (1)

Adverse Event < 24 wks n = 10* 24-48 wks n = 6 > 48 wks n = 7 Total n = 23* (%) Diarrhea/colitis 3 5 8 (13) Respiratory disorders 5 5 (8) Rash 3 3 (5) Anemia 1 1 2 (3) ALT/AST 1 1 (2) Other 2 4 2 8 (13)

Infections in first 48 weeks

• 67% - any Grade
• 23% - Grade ≥ 3
• Grade ≥ 3 pneumonia in 14%

Idelalisib + Rituximab: Discontinuations

*patients may have > 1 AE

*ITT analysis of primary + extension study Extension study assessments based on standard of care

Idelalisib + Rituximab in Frontline CLL: Progression-Free Survival*

5 10 15 20 25 30 20 40 60 80 100

All Patients N=64 TP53 mutation/ Del (17p) N=9

BL

Months Probability of PFS

Idelalisib + R

(N = 64)

PFS at 24 months: 93%

Lamana et al. iwCLL 2013

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Study 116: Randomized, Double‐Blind, Placebo‐Controlled

Extension Single‐Agent Therapy

Extension Study 117

Randomized Combination Therapy Continuing Single‐Agent Therapy

Primary Study 116

Arm A (N=11 0) Arm B (N=11 0) Idelalisib (150 mg BID) Placebo (BID) Rituximab (6 months) Rituximab (6 months) Screening

Idelalisib

(150 mg BID)

Idelalisib

(300 mg BID) Rituximab administration

• 375 mg/m2, then 500 mg/m2 Q2W x 4,

then 500 mg/m2 Q4W x 3 Clinical Endpoints

• Primary: PFS as assessed by IRC
• Events: Disease progression or death
• Secondary: ORR, LNR, OS

Disease Progression Planned interim analyses at 50% and 75% of events

Criteria Requirement

Relapsed CLL

• CLL progression <24 months since last therapy
• Treatment warranted according to IWCLL

criteria Lymphadenopathy

• Presence of ≥1 measurable nodal lesion

Prior therapies

• ≥ 1 anti-CD20 antibody containing therapy
• r ≥ 2 prior cytotoxic therapies

Appropriate for non-cytotoxic therapy

• CIRS score >6
• r creatinine clearance <60 ml/min (≥30

mL/min)

• r Grade 3/4 neutropenia or thrombocytopenia

due to prior myelotoxicity Bone marrow function

• Any grade anemia, neutropenia or

thrombocytopenia allowed Karnofsky score

• ≥40

Study 116: Key Eligibility

Furman et al NEJM 2014

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Primary Endpoint: Progression-Free Survival

AE, n (%) IDELA + R (N=110) Placebo + R (N=107) Any Grade Grade  3 Any Grade Grade  3 Patients with any AE 100 (91) 62 (56) 101 (94) 51 (48) Pyrexia 32 (29) 3 (3) 17 (16) 1 (1) Fatigue 26 (24) 3 (3) 29 (27) 2 (2) Nausea 26 (24) 23 (22) Chills 24 (22) 2 (2) 17 (16) Diarrhea 21 (19) 4 (4) 15 (14) Infusion-related reaction 17 (16) 30 (28) 4 (4) Cough 16 (15) 27 (25) 2 (2) Decreased appetite 13 (12) 9 (8) 1 (1) Constipation 13 (12) 12 (11) Vomiting 13 (12) 8 (8) Dyspnea 12 (11) 2 (2) 20 (19) 3 (3) Rash 11 (10) 2 (2) 6 (6) Night sweats 11 (10) 8 (8)

Adverse Events ≥10% In Either Study Arm

Furman et al NEJM 2014

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ABT-199: Potent and Selective Bcl-2 Inhibition

• Small molecule, orally bioavailable
• High affinity for Bcl-2, lower affinity for Bcl-xL, Mcl-1
• >100-fold improved functional selectivity for Bcl-2 over Bcl-xL in

assays with tumor cell lines

Souers AJ, et al. Nat Med. 2013;19:202-208. Affinity Cellular Efficacy, EC50, nM TR FRET Ki, nM FL5.12, 3% FBS Human Tumor Cell Lines, 10% HS Agents Bcl-2 Bcl-xL Bcl-w Mcl-1 Bcl-2 Bcl-xL Functional Selectivity RS4;11 (Bcl-2) H146 (Bcl-xL) Navitoclax 0.04 0.05 7 > 224 20 13 0.6 110 75 ABT-199 < 0.01 48 21 > 444 4 261 65 12 3600

Dosing Schedule of ABT-199: Dose Escalation Schematic

*3 patients (1 each in cohorts 2, 3, & 5) received ABT-199 20 mg as initial dose. **Step-up doses range from 100 to 400 mg. DCD = Designated Cohort Dose

c

Lead‐in to Designated Cohort Dose ‐ Expanded Safety Cohort Dose Escalation Scheme

Seymour et al. ASH 2013

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Serious AEs* Possibly/Probably ABT-199 Related

Patients, n (%)

Febrile neutropenia (G3) 3 (5) Tumor lysis syndrome (G3) 3 (5) Sudden Death (G5)** 1 (2) Viral URTI (G3) 1 (2) Clostridium difficile infection (G3) 1 (2) Escherichia sepsis (G3) 1 (2) Influenza (G3) 1 (2) Pneumonia (G3) 1 (2) Sepsis (G3) 1 (2) URTI (G3) 1 (2) Fluid overload (G3) 1 (2) Renal failure acute (G3) 1 (2) Pulmonary embolism (G4) 1 (2)

*More than one SAE may have occurred in the same person; G = Grade; URTI = Upper respiratory tract infection **In the setting of tumor lysis syndrome.

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Responses of ABT-199 Treated Patients

Responses

All n (%) n = 56 del (17p)** n (%) n = 17 Fludarabine Refractory** n (%) n = 27

Overall response rate 47 (84) 14 (82) 24 (89)

Complete response 13 (23) 2 (12) 6 (22) Partial response* 34 (61) 12 (71) 18 (67) Stable disease 4 (7) 1 (6) 2 (7) Disease progression 1 (2) 1 (6) ‐ D/C Prior to first (W6) assessment 4 (7) 1 (6) 1 (4)

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*3 patients had confirmatory CT imaging assessments at less than an 8 week interval (5, 6, and 7 weeks). **10 patients were both del(17p) and fludarabine refractory.

• As of September 30, 2013, response data is limited for patients in the safety expansion

(SE) cohort (n = 11)

• 4 patients in the SE cohort had a PR at their first scan, but were not evaluable
• Evaluable patients had 2 CT scans, performed approximately 8 weeks apart
• 9/13 in CR assessed for MRD: 5 MRD

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Conclusions

• Several exciting new agents in clinical

trials

• More selective than chemotherapy but

not without toxicity

• Ibrutinib FDA approved - 2014
• Idelalisib will likely be approved later

this year

• Already 2nd generation P13K and BTK

inhibitors in clinical trials as well as SYK inhibitors